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Proteins without signal peptides can still be released into extracellular space via ER/Golgi-independent unconventional secretory pathway(s) that remain to be revealed. A class of leaderless proteins including the pro-inflammatory cytokine interleukin-β (IL-β) is processed in the cytosol by proteolytic machineries such as the inflammasome prior to secretion. Studies in yeast uncovered a new unconventional secretory pathway that is dependent on GRASP (Golgi Reassembly and Stacking Protein) and autophagy proteins. The purpose of this work was to determine whether this autophagy-based unconventional secretory pathway (secretory autophagy) is conserved in mammals, how this secretory autophagy differs from the traditional degradative autophagy, and how GRASP intersects with the autophagy pathways. Here, we provide the first evidence that autophagy mediates unconventional secretion of IL-β in an inflammasome, GRASP55, and Rab8-dependent manner in mouse bone marrow-derived macrophages, a route which also applies to IL-18 and non-inflammasome substrate HMGB1. GRASP55 was also found to be mediating autophagosome formation possibly making secretory autophagosomes. We also give initial insights to the divergence between degradative autophagy and this secretory autophagy pathway, which preferentially utilizes some of the autophagy-related proteins, LC3A, GABARAP, and p62, but not LC3B, NBR1, TBK1, and ULK1. We also discuss the way that GRASP55, the conserved player of unconventional secretion, negatively regulates removal of damaged mitochondria by mitophagy, which might be due to competition between secretory and degradative autophagy. Taken together, these data indicate there is a conserved, unconventional secretory pathway involving GRASP and autophagy. It also suggests that although secretory and degradative autophagy share some core components, secretory autophagy also involves specialized molecular machinery to execute its unconventional secretory function and balance wit

Proteins without signal peptides can still be released into extracellular space via ER/Golgi-independent unconventional secretory pathway(s) that remain to be revealed. A class of leaderless proteins including the pro-inflammatory cytokine interleukin-1β (IL-1β) is processed in the cytosol by proteolytic machineries such as the inflammasome prior to secretion. Studies in yeast uncovered a new unconventional secretory pathway that is dependent on GRASP (Golgi Reassembly and Stacking Protein) and autophagy proteins. The purpose of this work was to determine whether this autophagy-based unconventional secretory pathway (secretory autophagy) is conserved in mammals, how this secretory autophagy differs from the traditional degradative autophagy, and how GRASP intersects with the autophagy pathways. Here, we provide the first evidence that autophagy mediates unconventional secretion of IL-1β in an inflammasome, GRASP55, and Rab8-dependent manner in mouse bone marrow-derived macrophages, a route which also applies to IL-18 and non-inflammasome substrate HMGB1. GRASP55 was also found to be mediating autophagosome formation possibly making secretory autophagosomes. We also give initial insights to the divergence between degradative autophagy and this secretory autophagy pathway, which preferentially utilizes some of the autophagy-related proteins, LC3A, GABARAP, and p62, but not LC3B, NBR1, TBK1, and ULK1. We also discuss the way that GRASP55, the conserved player of unconventional secretion, negatively regulates removal of damaged mitochondria by mitophagy, which might be due to competition between secretory and degradative autophagy. Taken together, these data indicate there is a conserved, unconventional secretory pathway involving GRASP and autophagy. It also suggests that although secretory and degradative autophagy share some core components, secretory autophagy also involves specialized molecular machinery to execute its unconventional secretory function and balance, Biomedical Sciences, Doctoral, University of New Mexico. Biomedical Sciences Graduate Program, Deretic, Vojo, Wilson, Bridget, Prossnitz, Eric, Orlando, Robert