Facets of Autophagy Based Unconventional Protein Secretion–The Road Less Traveled

Abstract

Unconventional protein secretion (UCPS) of leaderless proteins bypasses the conventional endoplasmic reticulum (ER)-Golgi route. The proportion of UCPS in the secretome varies tremendously across eukaryotes. Interestingly, macroautophagy, an intracellular recycling process that is generally involved in cargo degradation, also participates in UCPS. This emerging field of secretory mode of autophagy is underexplored and has several unanswered questions regarding the composition of players, cargo, and the mechanisms that drive it. As secretomes vary considerably across cell types and physiological conditions, the contribution of secretory autophagy in healthy and pathophysiological states remain to be elucidated. Recent studies have begun to shed light on this enigmatic process.

Autophagy Drives Galectin-1 Secretion From Tumor-Associated Macrophages Facilitating Hepatocellular Carcinoma Progression

“…Thus, TLR2-mediated increase of ROS in TAMs might lead to generating cholesterol-rich MVBs for Gal-1 secretion via autophagy. On the other hand, specific recruitment of Rab8a and Sec22b in secretory autophagy while Rab8b and Stx17 are recruited in degradative autophagy has been observed ( Padmanabhan and Manjithaya, 2020 ). Here, we found the MVB/Rab11/VAMP7 axis but not Stx17 participating in secretory autophagy of Gal-1 in TAMs.…”

“…The autophagy process is controlled by a family of autophagy-related proteins (ATG) to mediate the package of cargo proteins in a double membraned autophagosome and their subsequent degradation by fusion with lysosomes. However, instead of being degraded, some cargo proteins can be secreted out by autophagy, in a process termed secretory autophagy ( Kawabata and Yoshimori, 2020 ; Padmanabhan and Manjithaya, 2020 ). One of the earliest examples of autophagy-dependent unconventional secretion described in mammalian cells is IL-1β which lacks a leader peptide and is processed through a cytoplasmic platform termed inflammasome ( Zhang et al, 2015 ).…”

“…Several vesicular trafficking regulators, including small GTPase Rab protein family and SNARE proteins, have been revealed to regulate secretory or degradative autophagy. For example, Rab11 participates in amphisome formation, and Rab8a mediates transporting amphisome to the plasma membrane, while syntaxin 17 (Stx17) and Rab8b are responsible for fusion of lysosome and autophagosome ( Amaya et al, 2015 ; Padmanabhan and Manjithaya, 2020 ). It is still unclear whether secretory autophagy is involved in Gal-1 secretion.…”

Altered protein secretion in Batten disease

“…2 ). Although the primary function of autophagy is to break down and recycle intracellular material, mounting evidence suggests it also participates in conventional and unconventional protein secretion ( New and Thomas, 2019 ; Cavalli and Cenci, 2020 ; Padmanabhan and Manjithaya, 2020 ). While the mechanisms regulating autophagy-dependent secretion are not fully understood, autophagy (ATG) genes ( Box 1 ), autophagosomes ( Box 1 ) and multivesicular bodies ( Box 1 ) are thought to play important roles ( Duran et al, 2010 ; Manjithaya et al, 2010 ; Chen et al, 2017 ).…”

Beyond Self-Recycling: Cell-Specific Role of Autophagy in Atherosclerosis

“…Besides the catalytic function, the autophagy machinery also mediates a range of noncanonical functions [ 51 , 52 ]. Indeed, given its multifaceted role in cellular homeostasis, autophagy lies at an interface with many cellular pathways, including cell death, cell cycle, and immune signaling [ 33 , 53 ].…”