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Secretion

Secretion is the biological process by which living cells produce and release specific molecules, such as proteins, hormones, enzymes, and fluids, from their interior to the extracellular space or external environment, enabling essential functions like intercellular communication, nutrient transport, and waste removal.^[1]^[2] This process is fundamental to cellular physiology across eukaryotes and prokaryotes, occurring through specialized pathways that ensure precise regulation and targeted delivery of secreted products.^[3] In multicellular organisms, secretion supports critical systems including the endocrine and exocrine glands, where substances like insulin or digestive enzymes are expelled to maintain homeostasis.^[4] At the cellular level, secretion primarily involves the secretory pathway, beginning with synthesis in the rough endoplasmic reticulum (RER), followed by processing and packaging in the Golgi apparatus, and culminating in vesicle transport to the plasma membrane for exocytosis.^[2] Exocytosis can be constitutive, occurring continuously to release proteins for structural or signaling roles, or regulated, triggered by stimuli like calcium ions to discharge contents such as neurotransmitters in neurons.^[5] Key proteins that mediate vesicle-plasma membrane fusion include SNARE proteins.^[6] In prokaryotes, secretion systems like type III or IV machineries allow bacteria to export virulence factors or nutrients, highlighting secretion's role in microbial pathogenesis and symbiosis.^[7] The importance of secretion extends to health and disease; disruptions can lead to conditions such as diabetes (impaired insulin secretion) or cystic fibrosis (defective chloride ion secretion), while therapeutic strategies often target secretory pathways to modulate immune responses or drug delivery.^[2] Examples of secreted products include hormones like adrenaline for stress responses, antibodies from plasma cells for immunity, and exosomes—small vesicles carrying nucleic acids for cell-to-cell signaling.^[4] Overall, secretion underscores the dynamic interplay between cellular machinery and organismal function, with ongoing research revealing molecular details through techniques like atomic force microscopy.^[3]

General Concepts

Definition and Classification

Secretion refers to the directed and active transport of substances, such as proteins, lipids, and metabolites, from the interior of a cell to the extracellular space or external environment, distinguishing it from passive diffusion or uncontrolled cell lysis that releases contents indiscriminately.^[8] This process is essential for cellular communication, nutrient release, and environmental interaction across all domains of life, involving specialized molecular machinery to ensure specificity and energy dependence.^[9] In eukaryotes, secretion is broadly classified into constitutive and regulated pathways based on the timing and control of release. Constitutive secretion occurs continuously, delivering proteins and lipids via vesicles that fuse with the plasma membrane without external stimuli, supporting ongoing cellular maintenance such as membrane renewal.^[10] In contrast, regulated secretion involves storage of substances in secretory granules, with release triggered by specific signals like calcium influx, enabling rapid responses such as neurotransmitter discharge in neurons.^[11] Eukaryotic pathways are further categorized as classical or non-classical: classical secretion relies on an N-terminal signal peptide directing proteins through the endoplasmic reticulum (ER) and Golgi apparatus via vesicle-mediated exocytosis, while non-classical pathways bypass the Golgi and are independent of signal peptides, often involving direct translocation across the plasma membrane.^[12] Prokaryotes employ distinct secretion systems, classified from Type I (T1SS) to Type IX (T9SS) or beyond, based on their structural components, energy sources, and substrates translocated across one or both membranes.^[7] These systems vary in complexity; for instance, T1SS uses ATP-binding cassette (ABC) transporters to couple energy from ATP hydrolysis directly to protein export across the cell envelope in a single step, common in Gram-negative bacteria for exporting toxins or adhesins.^[7] Exocytosis, characterized by vesicle fusion with the plasma membrane, serves as a hallmark mechanism in eukaryotes for both constitutive and regulated secretion, exemplified briefly by insulin release from pancreatic beta cells in response to glucose stimulation.^[13] The term "secretion" originated in 17th-century physiology from the Latin secretio, meaning separation or release, initially describing glandular functions in animals.^[14] Its conceptualization in modern cell biology was formalized in the mid-20th century through electron microscopy studies by George Palade in the 1950s, which visualized the vesicular transport pathway and established the foundational model for protein secretion.^[15]

Biological Roles and Importance

Secretion plays a pivotal role in nutrient acquisition across organisms, as cells release digestive enzymes such as amylases, proteases, and lipases into the extracellular environment to break down complex macromolecules into absorbable forms.^[16] In bacteria, this process is crucial for scavenging nutrients from limited environments, where secreted enzymes enable the hydrolysis of polymers like starch or proteins, supporting growth under nutrient stress.^[17] Similarly, in multicellular organisms, pancreatic and salivary secretions facilitate the digestion of food, ensuring efficient nutrient uptake for energy and biosynthesis.^[18] Beyond nutrition, secretion underpins intercellular communication through the release of signaling molecules like hormones and neurotransmitters, which coordinate physiological responses over short and long distances. Hormones, secreted by endocrine glands into the bloodstream, regulate diverse processes including metabolism, growth, reproduction, and stress responses in multicellular organisms.^[19] Neurotransmitters, released at synapses, enable rapid neural signaling for functions such as muscle contraction and sensory processing.^[20] In defense mechanisms, organisms secrete antimicrobial compounds and toxins; for instance, bacteria produce antibiotics like bacteriocins to inhibit competitors, while immune cells release cytokines and antimicrobial peptides to combat pathogens.^[21] Additionally, secretion contributes to structural integrity by exporting extracellular matrix (ECM) components such as collagens, fibronectin, and proteoglycans, which provide mechanical support, guide cell migration, and maintain tissue architecture during development and repair.^[22] In multicellular organisms, secretion is essential for maintaining tissue homeostasis and facilitating development, as secreted factors like growth factors and ECM proteins regulate cell proliferation, differentiation, and extracellular signaling to ensure organ function and repair.^[23] For microbes, secretion drives pathogenesis by delivering virulence factors that manipulate host cells, promotes symbiosis through nutrient exchange in mutualistic interactions, and enables biofilm formation by secreting adhesins and matrix polysaccharides that protect communities from environmental stresses and antibiotics.^[24] Defects in secretion, such as misfolding and impaired trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, underlie diseases like cystic fibrosis, leading to defective ion and fluid secretion in epithelial tissues and chronic infections.^[25] Bacterial secretion systems exacerbate antibiotic resistance by facilitating the horizontal transfer of resistance genes via conjugation and through the action of efflux pumps that expel drugs, contributing to an estimated global economic burden of approximately US$900 billion annually (as of 2019 estimates), including hospital costs and productivity losses from resistant infections.^[26]^[27] Evolutionarily, secretion systems represent ancient innovations, with bacterial type III systems tracing back over a billion years and diversifying through horizontal gene transfer, which has accelerated adaptation and ecological niches across prokaryotes.^[28]

Eukaryotic Secretion

Classical Secretory Pathway

The classical secretory pathway in eukaryotic cells is the primary mechanism for exporting proteins destined for secretion or membrane insertion, involving a series of vesicular transport steps from the endoplasmic reticulum (ER) to the plasma membrane. This pathway was elucidated through pioneering pulse-chase experiments in the 1960s using pancreatic exocrine cells, where radiolabeled amino acids tracked the movement of secretory proteins from the rough ER through the Golgi apparatus to zymogen granules and eventual exocytosis.^[29] Approximately one-third of the eukaryotic proteome enters this pathway, encompassing soluble secreted proteins and transmembrane proteins.^[30] Proteins enter the pathway during synthesis on cytosolic ribosomes, where an N-terminal signal peptide—typically 15-30 hydrophobic amino acids—directs the nascent polypeptide to the ER via the signal recognition particle (SRP) and its receptor.^[31] In the ER lumen, proteins undergo folding assisted by chaperones like BiP and calnexin, along with post-translational modifications such as N-linked glycosylation (addition of core mannose-rich oligosaccharides) and formation of disulfide bonds by oxidoreductases like PDI, which stabilize structure and prevent aggregation.^[32] Properly folded proteins are then packaged into COPII-coated vesicles at ER exit sites; the coat assembles via the GTPase Sar1 recruiting Sec23/24 (inner coat for cargo selection) and Sec13/31 (outer coat for curvature), forming ~60-80 nm vesicles that bud from the ER and fuse with the cis-Golgi via SNARE-mediated docking.81577-9) Within the Golgi, proteins traverse the stacks via cisternal maturation or vesicular transport, with COPI coats (assembled by ARF1 GTPase and coatomer) mediating intra-Golgi retrograde trafficking to retrieve ER residents and recycle components.^[33] At the trans-Golgi network, cargo is sorted into secretory vesicles or post-Golgi carriers, often guided by Rab GTPases (e.g., Rab6 for Golgi exit, Rab8 for plasma membrane targeting) that recruit effectors for tethering and ensure specificity.^[34] These vesicles undergo microtubule-based transport and fuse with the plasma membrane through exocytosis, driven by trans-SNARE complexes (e.g., v-SNARE VAMP2 on vesicles pairing with t-SNAREs syntaxin-4 and SNAP-23 on the plasma membrane) and triggered by Ca²⁺ influx, which activates synaptotagmin as a clamp to release fusion energy. This regulated fusion releases contents extracellularly, completing the pathway.

Non-Classical Secretion Pathways

Non-classical secretion pathways in eukaryotes enable the export of proteins that bypass the endoplasmic reticulum (ER) and Golgi apparatus, distinguishing them from the classical secretory route. These pathways primarily handle leaderless proteins lacking N-terminal signal peptides, allowing direct translocation or vesicular transport to the plasma membrane. Often triggered by cellular stress or specific signals, they rely on energy sources such as ATP hydrolysis or membrane potentials rather than vesicular trafficking through the Golgi.^[35] These mechanisms were first identified in the 1990s through studies on proteins like fibroblast growth factor 2 (FGF2) and interleukin-1β (IL-1β), which were found in extracellular spaces despite lacking signal peptides.^[36] Non-classical pathways account for a significant portion of secreted proteins lacking classical signals, with estimates of approximately 50% in plants and varying proportions in other eukaryotes (e.g., mammals).^[37] facilitating rapid responses such as inflammation or stress adaptation.^[37] Four main types of non-classical secretion have been delineated based on their mechanisms. Type I involves ABC transporter-mediated translocation across the plasma membrane, powered by ATP hydrolysis. For instance, the macrophage migration inhibitory factor (MIF) is exported via ABC transporters in mammalian cells, while the yeast a-factor mating pheromone uses the Ste6 ABC transporter; the cystic fibrosis transmembrane conductance regulator (CFTR), itself an ABC transporter, exemplifies non-classical trafficking to the membrane under stress conditions, though it functions primarily as a chloride channel.^[38]^[39]00819-1) Type II secretion occurs through pore-forming mechanisms at the plasma membrane, independent of external energy input and driven by the protein's intrinsic properties. FGF2, for example, binds phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) in the inner leaflet, oligomerizes to form transient lipidic pores, and translocates to the extracellular space with assistance from heparan sulfate proteoglycans.31599-3) Similarly, the HIV Tat protein is exported via a comparable direct translocation route, enabling rapid dissemination during infection.^[40] In Type III, autophagy-related processes facilitate secretion by engulfing cytosolic proteins into double-membrane vesicles that fuse with the plasma membrane. IL-1β secretion in macrophages during inflammation exemplifies this, where the protein is loaded into autophagosomes under inflammatory cues like lipopolysaccharide stimulation, allowing swift cytokine release without ER involvement.^[40] This pathway highlights the role of non-classical routes in immune responses, with energy derived from autophagic machinery. Type IV utilizes multivesicular bodies (MVBs) derived from endosomes, where proteins are sorted into intraluminal vesicles that are released extracellularly upon MVB fusion with the plasma membrane, often as exosomes. This mechanism secretes leaderless proteins like galectins and fibroblast growth factor 1 (FGF1), bypassing Golgi processing and enabling targeted delivery in processes such as wound healing.^[41] A core feature of these pathways is their operation without ER quality control, which poses challenges including the risk of secreting misfolded proteins and unclear selectivity for cargo recognition, as proteins must interact specifically with transporters, pores, or vesicular components.31599-3) Despite these hurdles, non-classical secretion supports essential functions, such as the rapid export of inflammatory mediators, underscoring its physiological importance.^[36]

Physiological Examples in Human Tissues

In human physiology, secretion plays a pivotal role in maintaining homeostasis across various tissues, with the endocrine system exemplifying regulated exocytosis through insulin release from pancreatic beta cells. Insulin, a peptide hormone synthesized in the endoplasmic reticulum and packaged into secretory granules, is secreted in response to elevated blood glucose levels, facilitating glucose uptake in target cells via binding to insulin receptors. This process involves calcium-triggered fusion of granules with the plasma membrane, ensuring precise control over metabolic regulation.^[42] Exocrine secretion is illustrated in the salivary glands, where acinar cells release amylase, a digestive enzyme that hydrolyzes starches in the oral cavity. This constitutive and stimulated secretion occurs via the classical pathway, with amylase packaged in zymogen granules and discharged into ducts to mix with saliva, aiding initial carbohydrate digestion. The pancreas further exemplifies exocrine function, secreting approximately 1-2 liters of enzyme-rich fluid daily to support intestinal nutrient breakdown.^[43]^[44] In the immune system, plasma cells derived from B lymphocytes secrete antibodies, primarily immunoglobulin A in mucosal tissues like salivary glands, to neutralize pathogens and modulate local immunity. These antibodies are produced through the classical secretory pathway, with high-volume release enabling rapid humoral responses during infection.^[45] Neuronal tissues demonstrate ultrafast regulated secretion, as synaptic vesicles in presynaptic terminals release neurotransmitters such as glutamate or acetylcholine upon action potential arrival. This exocytosis occurs on a millisecond timescale, mediated by synaptotagmin as the calcium sensor that synchronizes SNARE complex assembly for rapid vesicle fusion, ensuring precise signal transmission across synapses.^[46]^[47] Disruptions in secretion contribute to major disorders; in type 1 diabetes, autoimmune destruction of beta cells impairs insulin exocytosis, leading to hyperglycemia and metabolic dysregulation.^[42] In Alzheimer's disease, amyloid-beta peptides are secreted via non-classical pathways independent of the endoplasmic reticulum-Golgi route, promoting plaque formation and neuroinflammation. Cystic fibrosis arises from CFTR mutations that dysregulate chloride transport, resulting in mucin hypersecretion and viscous airway mucus that obstructs clearance and fosters chronic infections.^[48]^[49] Classical and non-classical pathways interplay in human tissues, particularly during inflammation, where leaderless cytokines like interleukin-1β are released via non-classical mechanisms from immune cells, amplifying responses without signal peptides.^[50]

Bacterial Secretion

Common Translocation Systems Across Bacteria

Bacterial secretion relies on conserved translocation systems that span the cytoplasmic membrane, enabling the export of proteins essential for cell envelope biogenesis, nutrient acquisition, and environmental adaptation. Among these, the Sec and Tat pathways represent the primary mechanisms for protein translocation across this membrane in both Gram-negative and Gram-positive bacteria, as well as archaea. These systems handle the majority of exported proteins, with the Sec pathway accounting for the translocation of unfolded or nascent polypeptides and the Tat pathway specializing in fully folded substrates. Together, they are crucial for the proper localization of approximately 30% of a typical bacterial proteome, underscoring their universal importance in prokaryotic physiology.^[7]^[51] The Sec pathway facilitates post-translational translocation of proteins across the cytoplasmic membrane through the SecYEG translocon, a heterotrimeric complex embedded in the lipid bilayer. Proteins destined for export via this route are synthesized as precursors bearing an N-terminal signal peptide, typically 20-30 amino acids long with a hydrophobic core, which directs the preprotein to the Sec machinery. The chaperone SecB maintains the precursor in an export-competent, unfolded state before handover to SecA, a peripheral ATPase that docks onto SecYEG and drives translocation by cycling through ATP-binding and hydrolysis cycles, pushing the polypeptide through the channel in a stepwise manner.^[52]^[53]^[54] Signal peptidase then cleaves the signal peptide upon emergence into the periplasm (in Gram-negatives) or extracellular space (in Gram-positives). The Sec system was first identified in the 1980s through genetic screens in Escherichia coli that isolated conditional lethal mutants defective in protein export, such as secA and secY alleles, which accumulate precursors and exhibit pleiotropic secretion defects unless grown under permissive conditions.^[51] These mutants are often lethal without supplementation to bypass periplasmic protein requirements, highlighting the pathway's essentiality for viability.^[51] In contrast, the Tat pathway translocates fully folded proteins across the energized cytoplasmic membrane, powered primarily by the proton motive force (ΔpH) rather than ATP hydrolysis. Substrates are recognized by a twin-arginine signal peptide motif (S/T-R-R-x-F-L-K) at their N-terminus, which engages the TatABC translocon complex, where TatA forms the pore and TatB/C handle substrate binding and quality control. Unlike the Sec system, Tat accommodates proteins that have already assembled cofactors or oligomeric structures in the cytoplasm, such as enzymes with iron-sulfur clusters or molybdopterin, due to its tolerance for folded states and built-in proofreading mechanisms that prevent export of misfolded cargo.^[55]^[56] This pathway is particularly vital for oxidative stress responses and pathogenesis in certain bacteria, where cofactor maturation must precede translocation.^[57] Both the Sec and Tat pathways are highly conserved across bacteria and archaea, with homologs present in virtually all sequenced prokaryotic genomes, reflecting their ancient origins and indispensable roles in protein targeting. The Sec translocon, in particular, is ubiquitous and handles the bulk of membrane and extracellular protein traffic, while Tat provides a complementary route for specialized, folding-dependent exports. Disruptions in either system lead to severe fitness defects, as seen in essentiality studies where SecYEG depletion halts growth, emphasizing their foundational position upstream of more specialized secretion machineries.^[7]^[58]

Secretion Systems in Gram-Negative Bacteria

Gram-negative bacteria possess a double-membrane envelope, consisting of an inner cytoplasmic membrane, a peptidoglycan-containing periplasmic space, and an outer membrane, which necessitates specialized secretion systems to transport proteins across both barriers into the extracellular environment or directly into host cells. These systems, primarily types I through VI, along with types VIII and IX, enable the export of diverse substrates such as toxins, enzymes, and effectors, playing crucial roles in pathogenesis, nutrient acquisition, and interbacterial competition. Unlike the general Sec and Tat pathways that deliver proteins to the periplasm, these dedicated systems couple to inner membrane translocons and span the entire envelope, often utilizing ATP hydrolysis or proton motive force (PMF) as energy sources.^[59]^[60] Secretion systems in Gram-negative bacteria are classified as one-step or two-step based on whether they transport substrates directly from the cytoplasm to the exterior (one-step) or via an intermediate in the periplasm (two-step). One-step systems, including types I, III, IV, and VI, form continuous conduits across both membranes, preventing periplasmic exposure and allowing secretion of folded proteins or macromolecules without unfolding. Two-step systems, such as types II, V, VIII, and IX, first utilize the Sec or Tat pathways to translocate unfolded substrates to the periplasm, followed by outer membrane translocation. All systems must navigate the peptidoglycan layer, often through enzymatic degradation or structural adaptations like secretins that form β-barrel pores in the outer membrane. Pathogenic Gram-negative bacteria typically encode multiple such systems, with species like Pseudomonas aeruginosa possessing up to five of the six main types (I–VI), sometimes in multiple copies, to coordinate virulence. Recent structural studies using cryo-electron microscopy (as of 2024) have revealed detailed mechanisms of type IV and VI systems, including pilus assembly and effector delivery.^[59]^[60]^[61]^[62]^[63] Key distinctions among these systems lie in their energy sources, substrates, and architectures. The type I secretion system (T1SS) is a one-step ATP-driven ABC exporter that secretes large unfolded proteins like hemolysins and proteases directly across both membranes using a tripartite complex of inner membrane ABC transporter, membrane fusion protein, and outer membrane TolC channel.^[59] The type II secretion system (T2SS), a two-step process powered by ATP via a pseudopilus assembly, exports folded periplasmic proteins such as lipases and chitinases through 12–15 core proteins including the outer membrane secretin.^[60] The type III secretion system (T3SS) employs a one-step needle-like injectisome energized by ATP and PMF to deliver effector proteins into eukaryotic host cells; it evolved from the flagellar export apparatus through gene duplication and modification of conserved components like the ATPase.^[59] The type IV secretion system (T4SS) is versatile, functioning in one- or two-step modes with ATP-driven assembly to transfer DNA (conjugation) or inject proteins like CagA from Helicobacter pylori across membranes via a core complex of 11–12 proteins.^[60] Type V (T5SS), a two-step autotransporter, relies on Sec-mediated periplasmic delivery followed by self-insertion of the passenger domain through a β-barrel translocator domain in the outer membrane, secreting adhesins and proteases without additional energy input beyond folding.^[59] The type VI secretion system (T6SS), a one-step contractile phage tail-like structure powered by ATP, propels effectors and toxins to puncture neighboring cells or hosts, aiding in competition and virulence.^[60] Type VIII (T8SS) facilitates two-step secretion of amyloid fibers like curli in Enterobacteriaceae, using a chaperone-usher pathway for assembly on the cell surface to promote biofilm formation.^[60] Type IX (T9SS), prevalent in Bacteroidetes, is a two-step system that translocates diverse proteins to the outer membrane via a PorSS complex, powering motility and degrading complex substrates like chitin.^[60] These systems collectively ensure efficient envelope traversal, with outer membrane factors like lipopolysaccharides influencing assembly and function.^[59]

Secretion Systems in Gram-Positive Bacteria

Gram-positive bacteria feature a single cytoplasmic membrane enveloped by a thick peptidoglycan layer, which simplifies protein export compared to the dual-membrane architecture of Gram-negative counterparts, as there is no outer membrane to traverse. Protein secretion primarily relies on the conserved Sec and Tat translocase systems to cross this membrane, with the Sec pathway exporting unfolded preproteins via a signal peptidase-cleaved N-terminal signal peptide, and the Tat pathway handling fully folded proteins, often those with cofactors like molybdenum or iron-sulfur clusters. These systems are essential for nutrient acquisition, cell wall maintenance, and virulence factor deployment.^[7]^[64] In Firmicutes, a major phylum of Gram-positive bacteria, the secretome—comprising proteins destined for export—typically accounts for 12-42% of the proteome, with the majority routed through the Sec pathway and a smaller fraction via Tat. For instance, in Bacillus subtilis, approximately 300 proteins are predicted to use Sec-dependent export for functions like extracellular enzyme production. Post-translocation, proteins must navigate the dense cell wall, where sortase enzymes covalently anchor many to peptidoglycan using the LPXTG sorting motif, enabling surface display of adhesins, enzymes, and toxins critical for biofilm formation and host colonization. Class A sortases, such as SrtA in Staphylococcus aureus, recognize this motif to link proteins to lipid II intermediates, which are then incorporated into the wall.^[65]^[66]^[67] Among specialized systems, the Type VII secretion system (T7SS) stands out, particularly in Actinobacteria like mycobacteria and in Firmicutes such as staphylococci and Listeria monocytogenes. Discovered in the early 2000s through analysis of the RD1 genomic region in Mycobacterium tuberculosis, T7SS exports small WXG100 superfamily proteins, including the virulence factors ESAT-6 and CFP-10, via an ATPase-driven mechanism involving core components like EccA (an AAA+ ATPase) and membrane channels formed by EccB-E. In tuberculosis pathogenesis, the ESX-1 variant of T7SS, encoded by the RD1 locus, facilitates phagosomal rupture in macrophages, promoting intracellular survival and granuloma formation. Recent 2020s research has identified T7SS variants in S. aureus, where they secrete EsxA-like effectors to inhibit competing bacteria and maintain membrane homeostasis against host antimicrobials like fatty acids, underscoring their role in polymicrobial environments and infection.^[68]^[69] Accessory secretion mechanisms complement these pathways, including holin proteins that form membrane pores to enable non-lytic export of endolysins or other substrates in tandem with cell wall hydrolases, as observed in Listeria species for virulence protein release without compromising cell integrity. Unlike the diverse Type I-VI systems in Gram-negative bacteria that navigate two membranes, Gram-positive secretion features fewer dedicated types, prioritizing efficient single-membrane crossing and robust cell wall anchoring to support their ecological niches.^[70]^[71]^[7]

Advanced Topics

Outer Membrane Vesicles in Gram-Negative Bacteria

Outer membrane vesicles (OMVs) are nanoscale, spherical structures naturally released by Gram-negative bacteria through the budding and fission of the outer membrane, serving as a mechanism for vesicle-based secretion distinct from traditional protein translocon systems. These vesicles encapsulate a diverse array of cargo, including lipids, proteins, nucleic acids, and metabolites, enabling bacteria to interact with their environment without direct cell-cell contact. OMVs typically range in diameter from 20 to 250 nm, with variations influenced by bacterial species and growth conditions.^[72]^[73] The biogenesis of OMVs involves blebbing of the outer membrane, driven by factors such as peptidoglycan (PG) asymmetry in the periplasm and lipopolysaccharide (LPS) modifications. Accumulation of misfolded proteins, PG fragments, or other periplasmic components creates osmotic pressure that promotes outward bulging of the outer membrane, while reduced cross-linking between the outer membrane and PG layer—mediated by proteins like Lpp or OmpA—facilitates vesicle pinching off. LPS plays a key role by undergoing remodeling, such as deacylation or enrichment with phospholipids, which increases membrane curvature and charge repulsion to drive vesiculation; for instance, in Pseudomonas aeruginosa, the pseudomonas quinolone signal (PQS) integrates into the membrane to further induce curvature. This process is non-lytic and occurs constitutively during growth, though production escalates under stress like nutrient limitation or antibiotic exposure.^[72]^[73]^[74] OMVs fulfill multiple functions critical to bacterial physiology and pathogenesis, including targeted cargo delivery, immune evasion, and horizontal gene transfer. They transport virulence factors, enzymes, and DNA to distant sites, such as host cells or other bacteria, enhancing infectivity; for example, OMVs from pathogenic strains deliver toxins like those in Vibrio cholerae to modulate host responses. In terms of protection from host immunity, OMVs act as decoys by binding antimicrobial peptides or antibodies, shielding the parent bacterium and disseminating immunomodulatory molecules via Toll-like receptor signaling. Additionally, OMVs facilitate horizontal transfer of genetic material, such as plasmids or chromosomal DNA, promoting antibiotic resistance dissemination across bacterial populations. Analogous to eukaryotic exosomes, OMVs enable long-range intercellular communication in prokaryotes.^[75]^[72]^[75] First observed in the 1960s through electron microscopy of Escherichia coli cultures, OMVs were initially dismissed as cellular debris but later recognized as purposeful secretions. They are particularly prominent in pathogens like Pseudomonas aeruginosa, where production rates are high under optimal conditions, aiding biofilm formation and chronic infections. OMVs can incorporate proteins from the type V secretion system (T5SS), such as autotransporters, allowing these to be packaged and delivered via vesicles rather than direct translocation, though OMV release remains mechanistically distinct from T5SS-mediated export. Therapeutically, post-2020 studies have highlighted OMVs' potential as vaccine adjuvants; for instance, engineered OMVs from Neisseria meningitidis detoxified of LPS have shown enhanced immunogenicity in eliciting protective antibodies against bacterial pathogens, with ongoing trials exploring their use in combination vaccines. As of 2025, meta-analyses indicate approximately 38% effectiveness of OMV-based meningococcal vaccines in preventing gonorrhea infections, supporting their role in broader antimicrobial strategies.^[76]^[73]^[77]^[72]^[78]

Evolutionary and Comparative Perspectives

The evolutionary origins of secretion systems trace back to the last universal common ancestor (LUCA), which is inferred to have possessed an ancestral Sec-like translocase system for protein export across membranes. Phylogenetic analyses indicate that components such as SecYEG were present in LUCA, enabling post-translational translocation of unfolded proteins, a mechanism conserved across bacteria and eukaryotes. This primordial system likely facilitated basic cellular functions like membrane biogenesis in an anaerobic, prokaryote-grade environment.^[79] In prokaryotes, specialized secretion systems evolved from these ancestral elements, with type III secretion systems (T3SS) and type IV secretion systems (T4SS) deriving from flagellar and type IV pilus assemblies, respectively. The non-flagellar T3SS, used for effector injection in pathogens, arose through exaptation of flagellar export machinery, adapting motility components for virulence without propulsion. Similarly, T4SSs originated from ancient conjugation machines involving type IV pili, enabling DNA and protein transfer, and diversified through modular assembly in diderm bacteria. Eukaryotic classical secretion, involving the endoplasmic reticulum (ER) and Golgi, represents a derived innovation, with its membrane-trafficking components emerging autogenously post-endosymbiosis, though the core Sec61 translocon homologs stem from bacterial ancestry acquired during mitochondrial integration.^[80]^[81]^[82] Comparative analyses reveal stark differences between prokaryotic and eukaryotic secretion: prokaryotes typically employ one- or two-step processes, such as direct periplasmic export in Gram-negatives or single-membrane translocation in Gram-positives, allowing rapid, energy-efficient deployment of effectors or adhesins. In contrast, eukaryotic secretion is a multi-organelle cascade involving ER folding, vesicular transport to the Golgi, and exocytosis, which supports complex glycosylation and quality control but increases energetic costs. Convergent evolution is evident in structures like T3SS injectisomes, which mimic molecular syringes for precise host-cell targeting, paralleling eukaryotic vesicle fusion but achieved through simpler, needle-like apparatuses. Horizontal gene transfer has profoundly shaped prokaryotic diversity, with systems like T6SS disseminated widely—present in approximately 25% of Gram-negative bacteria—facilitating niche adaptation and competition. Post-2015 studies further link T9SS evolution to gliding motility in Bacteroidota, where rotary motor components integrate secretion with propulsion via adhesin recycling.^[83]^[84] Recent cryo-EM structures from the 2020s have unified mechanistic insights across secretion types, revealing conserved energy-coupling motifs like ATP-driven contractions in T4SS and T6SS, which bridge prokaryotic diversity and inform evolutionary relationships. These advances highlight potential for synthetic biology, where engineered T3SS or T4SS deliver therapeutics directly into host cells, bypassing immune barriers for applications in cancer targeting and microbiome modulation.^[85]

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Inhibiting bacterial secretion systems in the fight against antibiotic ...
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Economic Impacts of Antimicrobial Resistance in Humans
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Bacterial type III secretion systems are ancient and evolved by ...
It is hypothesized that horizontal gene transfer has occurred much earlier and more frequently than previously inferred for TTSS genes and is, consequently, a ...
[28]
[PDF] George E. Palade - Nobel Lecture
x 26,000. Results obtained in pulse-chase experiments showed that the pathway fol- lowed by the secretory proteins leads from the rough endoplasmic reticulum to.
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[PDF] blobel-lecture.pdf - Nobel Prize
Recognition of the signal sequence by the Signal Recognition Particle (SRP). SRP 54 is a GTPase and is therefore marked G. As soon as the signal sequence has ...
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Computational Prediction of Protein Subcellular Locations in ...
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The Road Less Traveled? Unconventional Protein Secretion at ...
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[PDF] Molecular BioSystems - RSC Publishing
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[PDF] Pathways of Unconventional Protein Secretion - Hubrecht Institute
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Salivary gland function, development, and regeneration - PMC
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Neurotransmitter Release: The Last Millisecond in the Life of a ...
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Synaptotagmin Function Illuminated - PMC - PubMed Central
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The Amyloid-β Pathway in Alzheimer's Disease - PMC
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Unconventional Pathways of Secretion Contribute to Inflammation
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Sec- and Tat-mediated protein secretion across the bacterial ...
In bacteria, two major pathways exist to secrete proteins across the cytoplasmic membrane. The general Secretion route, termed Sec-pathway, catalyzes the ...
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SecA-Mediated Protein Translocation through the SecYEG Channel
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Bacterial Signal Peptides- Navigating the Journey of Proteins
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Twin-arginine translocase component TatB performs folding quality ...
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Fates of Sec, Tat, and YidC Translocases in Mitochondria and Other ...
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Bacterial protein secretion systems: Game of types
Summary of each segment:
[60]
Protein secretion systems in Pseudomonas aeruginosa: A wealth of ...
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Evolving understanding of the type VII secretion system in Gram ...
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Sec-Secretion and Sortase-Mediated Anchoring of Proteins in Gram ...
In this review, we describe the mechanisms for both Sec-dependent secretion and sortase-dependent assembly of proteins in the envelope of Gram-positive ...3. Sorting Reactions · 3.3. Sortase A-Catalyzed... · 3.6. Class C Sortase...<|control11|><|separator|>
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The type VII secretion system protects Staphylococcus aureus ...
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A holin/peptidoglycan hydrolase-dependent protein secretion system
We describe a protein secretion system that uses a holin membrane protein in tandem with a cell wall-editing enzyme to mediate the secretion of substrate ...
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The protein secretion systems in Listeria : inside out bacterial virulence
Table 1 summarizes the six protein secretion systems found in Listeria. Components of a Sec system, a Tat pathway, an FEA, an FPE, the holins, and a Wss, all ...
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Outer Membrane Vesicles of Gram-Negative Bacteria: An Outlook on ...
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Bacterial Outer Membrane Vesicles: From Discovery to Applications
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Decoration of Outer Membrane Vesicles with Multiple Antigens by ...
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The very early evolution of protein translocation across membranes
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The Non-Flagellar Type III Secretion System Evolved from the ...
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Biological Diversity and Evolution of Type IV Secretion Systems - PMC
The bacterial type IV secretion systems (T4SSs) are a highly functionally and structurally diverse superfamily of secretion systems found in many species of ...<|control11|><|separator|>
[78]
Evolution of the eukaryotic membrane-trafficking system: origin ...
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Type III secretion systems: the bacterial flagellum and the injectisome
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T6SS: A Key to Pseudomonas's Success in Biocontrol? - MDPI
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Oral delivery of therapeutic proteins by engineered bacterial type ...
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