How Multivesicular Bodies Affect Intercellular Communication

Cells rely on complex communication networks to regulate growth, immune responses, and homeostasis. A key player in this process is the multivesicular body (MVB), a specialized endosomal structure that facilitates cargo sorting and intercellular signaling. Understanding MVB function provides insight into their role in disease progression, immune modulation, and cellular waste management.

MVBs contribute significantly to intercellular communication by regulating exosome release and coordinating with other cellular pathways. Their interactions with lysosomes, autophagy, and extracellular vesicle production highlight their importance in maintaining cellular balance.

Formation In Early Endosomes

MVBs form within early endosomes, where membrane proteins and lipids are sorted. Early endosomes receive cargo from the plasma membrane through endocytosis and undergo maturation involving changes in membrane composition, pH, and protein recruitment. A defining feature of this transition is the inward budding of the endosomal membrane, creating intraluminal vesicles (ILVs), the hallmark of MVBs. This process is regulated by the endosomal sorting complexes required for transport (ESCRT) machinery, a multi-protein system that facilitates membrane deformation and vesicle scission.

The ESCRT system operates sequentially: ESCRT-0 clusters ubiquitinated cargo proteins, ESCRT-I and ESCRT-II drive membrane invagination, and ESCRT-III mediates vesicle scission. Accessory proteins such as ALIX and VPS4 assist in disassembling the ESCRT machinery after vesicle formation. Alternative ESCRT-independent pathways also exist, where ceramide and other sphingolipids induce membrane curvature and vesicle budding, ensuring redundancy in MVB biogenesis.

As early endosomes mature into late endosomes, the number of ILVs increases, reflecting progressive cargo sorting. Rab GTPases such as Rab5 and Rab7 regulate this transition, with Rab5 associated with early endosomes and Rab7 marking late endosomes. The interplay between these regulators determines whether MVBs fuse with lysosomes for degradation or proceed toward exocytic pathways. Tetraspanins such as CD63 and CD81 further influence ILV formation by stabilizing membrane domains.

Cargo Sorting Mechanisms

MVBs selectively sort molecular cargo, determining whether enclosed proteins, lipids, and RNA molecules are destined for degradation or secretion. Ubiquitinated cargo is recognized by ESCRT-0, which clusters these tagged proteins for inclusion into ILVs. Deubiquitinating enzymes (DUBs) add another layer of regulation by removing ubiquitin chains to rescue certain proteins from degradation.

Lipid composition also plays a role in cargo segregation. Ceramide promotes ILV formation by inducing membrane curvature, particularly in ESCRT-independent pathways. Phosphatidylinositol 3-phosphate (PI3P) recruits adaptor proteins that facilitate membrane remodeling, ensuring efficient cargo packaging.

Membrane-associated proteins such as tetraspanins refine cargo selection by organizing microdomains that preferentially incorporate specific proteins and nucleic acids. CD63 clusters transmembrane proteins into ILVs, while RNA-binding proteins selectively package microRNAs (miRNAs) and messenger RNAs (mRNAs), regulating the genetic content of extracellular vesicles. Evidence suggests that sequence motifs and secondary structures contribute to selective RNA enrichment within MVBs.

Exosome Release Pathways

Once cargo is sorted, MVBs either degrade or secrete their contents. Exosome release occurs when MVBs fuse with the plasma membrane, releasing ILVs into the extracellular space. Small GTPases such as Rab27a and Rab27b regulate MVB transport and docking at the cell surface, interacting with effector proteins like synaptotagmins and SNARE complexes to facilitate membrane fusion.

Lipid composition also influences exosome release. Cholesterol-rich microdomains provide structural support for vesicle budding and fusion, while lipid rafts in the plasma membrane guide MVBs to secretion sites. Ceramide further enhances membrane curvature, promoting exosome budding. Disruptions in lipid metabolism can alter exosome production, as seen in pathological conditions where aberrant lipid signaling affects vesicle secretion.

Cellular stress and environmental cues modulate exosome release. Hypoxia enhances secretion in tumor cells by upregulating Rab proteins and modifying endosomal trafficking. Calcium flux can also trigger rapid exosome release, particularly in neurons and immune cells, highlighting the dynamic regulation of vesicle output.

Coordination With Autophagic Machinery

MVBs and autophagy intersect in cellular recycling and secretion. Amphisomes—hybrid organelles formed when autophagosomes fuse with MVBs—can either degrade cargo via lysosomes or release it through extracellular vesicles. This balance allows cells to adapt to metabolic demands.

Rab7 regulates fusion events between MVBs, autophagosomes, and lysosomes, with higher Rab7 activity favoring degradation and lower activity shifting toward exosome release. Autophagy-related proteins (ATGs) such as ATG5 and ATG16L1 influence MVB function by modulating vesicle trafficking. Impaired autophagy can lead to MVB accumulation and excessive exosome secretion.

Role In Intercellular Signaling

MVBs mediate intercellular communication by facilitating exosome release, allowing the transfer of proteins, lipids, and nucleic acids that influence recipient cells. This signaling is crucial in tissue remodeling, differentiation, and stress adaptation. Cells fine-tune exosome composition to modulate target cell responses.

Exosomes are internalized by recipient cells through endocytosis, direct membrane fusion, or receptor-mediated interactions. The method of uptake determines downstream effects, with endocytosis integrating cargo into endosomal pathways and membrane fusion allowing direct cytoplasmic release. Surface proteins such as integrins and tetraspanins govern exosome targeting, ensuring specificity in signaling.

Interactions With Lysosomal Degradation

MVBs are directed toward lysosomal degradation when cargo is unnecessary for secretion, preventing cellular waste accumulation. Rab7 and SNARE proteins coordinate MVB-lysosome fusion, maintaining proteostasis by degrading damaged or misfolded proteins. Nutrient availability and cellular stress influence the balance between degradation and exosome release.

Disruptions in MVB-lysosome interactions are implicated in neurodegenerative diseases such as Parkinson’s and Alzheimer’s, where impaired trafficking leads to toxic protein accumulation. Lysosomal dysfunction can also cause excessive exosome secretion, as seen in lysosomal storage disorders. These disruptions underscore the importance of precise MVB-lysosome coordination.

Occurrence In Various Organisms

MVBs function across a wide range of organisms, from unicellular eukaryotes to complex multicellular systems. In yeast, they play a fundamental role in vacuolar degradation, with the ESCRT machinery highly conserved. Studies in Saccharomyces cerevisiae have provided insights into MVB biogenesis and protein sorting.

In plants, MVBs regulate hormone transport and pathogen defense, primarily fusing with vacuoles rather than the plasma membrane, emphasizing intracellular degradation over exosome-mediated communication. In invertebrates such as Drosophila melanogaster and Caenorhabditis elegans, MVBs influence developmental processes by guiding extracellular vesicle signaling. Their widespread presence highlights their fundamental role in cellular organization and intercellular interactions.