Autophagy in the regulation of protein secretion in immune cells

Protein secretion, a universal cellular feature, plays fundamental roles in innate and adaptive immunity. Indeed, the functional and phenotypic characterization of immune cells (e.g., effector lymphocytes or macrophages) entail quantitative and qualitative analyses of the expression of secretory proteins (e.g., cytokines, antibodies, ligands, and receptors). The conventional secretory pathway starts with an amino-terminal leader peptide driving nascent proteins into the endoplasmic reticulum (ER) for folding, maturation, and transportation to the plasma membrane through the Golgi apparatus. However, proteins lacking a leader sequence exist that are routed to the extracellular space or the plasma membrane through a variety of pathways collectively referred to as unconventional secretion. The field was pioneered in immune models, as epitomized by antibodies and interleukin-1β, paradigms, respectively, of conventional and unconventional protein secretion. Macroautophagy, by convention autophagy, is a fundamental cellular recycling strategy that dispatches unwanted cytoplasmic supramolecular structures to lysosomes upon isolation in double-membrane autophagosomes. Recent evidence heavily implicates autophagy in protein secretion. First, it participates in conventional secretion exerting both positive and negative effects and acting at multiple levels along the secretory pathway. Moreover, autophagy is instrumental to unconventional protein secretion through diverse mechanisms, including the regulation of intracellular inflammatory signaling and the trafficking strategies that allow secretion of leaderless proteins, leading to the recently coined concept of “secretory autophagy.” This chapter will describe the multiple mechanisms whereby autophagy interfaces with both conventional and unconventional protein secretion, with particular focus on their significance in innate and adaptive immunity.