LC3-dependent extracellular vesicle loading and secretion (LDELS)

Abstract

Accumulating evidence implicates various autophagy-related (ATG) proteins in cellular secretion. Recently, we identified a new secretory autophagy pathway in which components of LC3 conjugation machinery specify the incorporation of RNA binding proteins (RBPs) and small non-coding RNAs into extracellular vesicles (EVs), resulting in their secretion outside of cells. We term this process LC3-Dependent EV Loading and Secretion (LDELS). Importantly, LDELS is distinct from classical macroautophagy/autophagy because it requires components of the LC3 conjugation machinery, but not other ATGs involved in autophagosome formation. Because EVs have emerged as mediators of intracellular communication, our results provide new insight into how the autophagy machinery may influence the non-cell autonomous exchange of information between cells.

Keywords: Extracellular vesicles; RNA-binding proteins; autophagy; exosomes.

Figure 1.

Proposed model for LC3-dependent extracellular vesicle loading and secretion (LDELS). In addition to its functions in classical autophagy, LC3 specifies the secretion of proteins and RNAs in extracellular vesicles (EVs). During LDELS, LC3 and cargo delivered to the limiting membrane of multivesicular bodies (MVBs) undergo intralumenal budding and are released as extracellular vesicles upon fusion of the MVB with the plasma membrane. This novel autophagy-related secretory pathway requires the LC3-conjugation machinery, SMPD3 and LC3-dependent recruitment of NSMAF, which may locally drive ceramide production at the MVB membranes to facilitate EV biogenesis.