Beyond self-eating: The control of nonautophagic functions and signaling pathways by autophagy-related proteins

Cadwell, Ken; Debnath, Jayanta

The identification of conserved autophagy-related proteins (ATGs) that mediate bulk degradation of cytosolic material laid the foundation for breakthroughs linking autophagy to a litany of physiological processes and disease conditions. Recent discoveries are revealing that these same ATGs orchestrate processes that are related to, and yet clearly distinct from, classic autophagy. Autophagy-related functions include secretion, trafficking of phagocytosed material, replication and egress of viral particles, and regulation of inflammatory and immune signaling cascades. Here, we define common processes dependent on ATGs, and discuss the challenges in mechanistically separating autophagy from these related pathways. Elucidating the molecular events that distinguish how individual ATGs function promises to improve our understanding of the origin of diseases ranging from autoimmunity to cancer. and exit, antigen presentation, and ATG-mediated regulation of inflammatory and immune signaling. Importantly, these processes are fundamentally distinct from classic autophagy, and certainly, many can be construed as "noncanonical" functions for the individual ATG proteins that are involved. However, they are not by definition "noncanonical autophagy" in its strictest sense. Hence, to avoid confusion, the term "noncanonical" should be avoided when referring to these autophagy-related processes. In the following sections, we overview our current understanding of this diverse collection of autophagy-related processes that are distinct from classic autophagy.