Autophagy. 2025 Jun 12.
The autophagy mediator ATG16L1 forms part of a complex that is essential for MAP1LC3/LC3 lipidation and autophagosome formation in the canonical macroautophagic/autophagic pathway. However, ATG16L1 is also involved in unconventional activities where LC3 becomes lipidated in single-membrane structures unrelated to double-membrane autophagosomes. Such atypical activities usually require the C-terminal domain of the molecule that includes 7 WD40-type repetitions (WD40 domain, WDD). The WDD acts as a docking site for upstream inducers that engage the LC3 lipidation ability of ATG16L1 in alternative membrane compartments. Given that this domain is absent in the yeast Atg16 ortholog, an intriguing idea proposes that it was added to the primitive protein during evolution to perform new physiological roles required by the appearance of multicellularity. Identification of such atypical activities and their physiological implications at the organismal level are important issues that remain to be clarified. In a recent report we describe an unconventional autophagic pathway that restrains the immunogenic potential of apoptosis, a key feature of homeostatic and developmentally regulated cell death in multicellular organisms. This signaling route emanates from apoptotic mitochondria and induces the formation of single-membrane, LC3-positive vesicles through a mechanism that requires the WDD of ATG16L1. The induced vesicles sequester ATP to inhibit the amount of ATP released from apoptotic cells and, consequently, prevent the activation of co-cultured phagocytes. Thus, this is a pathway that contributes to maintain the immunosilent nature of apoptotic cell death.
Keywords: ATG16L1; ATP secretion; Apoptosis; BAK; immunogenic cell death; unconventional autophagy