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

Cadwell, Ken; Debnath, Jayanta

In addition to Beclin-1, multiple ATGs are required for LAP, including all key elements of the LC3 conjugation machinery (ATG3, ATG5, ATG7, ATG12, and ATG16L; Martinez et al., 2011) . Despite this common utilization of multiple ATGs, LAP is a mechanistically distinct process. During classic autophagy, LC3 lipidation occurs on early double membrane structures, called phagophores, and functions in the capture of autophagic cargo and to enhance the stability of the inner autophagosomal membrane (Stolz et al., 2014; Tsuboyama et al., 2016) . In contrast, during LAP, components of the autophagy conjugation machinery recruit LC3-II directly onto phagosomes, which are single membrane organelles. As a result, LAP does not use the ULK (unc-51-like autophagy activating kinase) complex that initiates canonical autophagy (Martinez et al., 2011) . Notably, similar pathways direct LC3 conjugation onto single-membrane organelles during entosis and macropinocytosis, two processes that also converge on the lysosome (Florey et al., 2011) . Furthermore, LAP uses a unique VPS34 complex, composed of Beclin-1, UVR AG, and Rubicon (RUB CN), a protein that is inhibitory to classic autophagy (Martinez et al., 2015) . Last, generation of reactive oxygen species (ROS) by NAD PH oxidase-2 (NOX2) has also been critically implicated in the control of LAP (Martinez et al., 2015) .