TMEM74 (ATG16L1) of 305 aas and 2 TMSs. An autosomal lysosomal protein that regulates autophagy (Yu et al. 2008). A coding polymorphism of human ATG16L1 (T300A) increases the risk of Crohn's disease and enhance susceptibility of ATG16L1 to caspase cleavage, and the ATG16L1 WD domain and linker regulate lipid trafficking to maintain plasma membrane integrityand  to limit influenza virus infection (Bone et al. 2025).  T300A also alters the ability of the C-terminal WD40-repeat domain of ATG16L1 to interact with an amino acid motif that recognizes this region. Such an alteration impairs the unconventional autophagic activity of TMEM59, a transmembrane protein that contains the WD40 domain-binding motif, and disrupts its normal intracellular trafficking and its ability to engage ATG16L1 in response to bacterial infection. TMEM59-induced autophagy is blunted in cells expressing the fragments generated by caspase processing of the ATG16L1-T300A risk allele, whereas canonical autophagy remains unaffected. Thus, the T300A polymorphism alters the function of motif-containing molecules that engage ATG16L1 through the WD40 domain, either by influencing this interaction under non-stressful conditions or by inhibiting their downstream autophagic signalling after caspase-mediated cleavage (Boada-Romero et al. 2016). Tethering ATG16L1 or LC3 induces targeted autophagic degradation of protein aggregates and mitochondria (Mei et al. 2023). The mammalian protein ATG16L1, primarily appreciated for its role in canonical autophagy and in noncanonical membrane atg8ylation processes, controls V-ATPase. An ATG16L1 knockout elevated V-ATPase activity, increased the V1 presence on endomembranes, and increased the number of acidified intracellular compartments (Yu et al. 2008). A coding polymorphism of human ATG16L1 (T300A) increases the risk of Crohn's disease and enhance susceptibility of ATG16L1 to caspase cleavage, and the ATG16L1 WD domain and linker regulate lipid trafficking to maintain plasma membrane integrityand  to limit influenza virus infection (Bone et al. 2025).  T300A also alters the ability of the C-terminal WD40-repeat domain of ATG16L1 to interact with an amino acid motif that recognizes this region. Such an alteration impairs the unconventional autophagic activity of TMEM59, a transmembrane protein that contains the WD40 domain-binding motif, and disrupts its normal intracellular trafficking and its ability to engage ATG16L1 in response to bacterial infection. TMEM59-induced autophagy is blunted in cells expressing the fragments generated by caspase processing of the ATG16L1-T300A risk allele, whereas canonical autophagy remains unaffected. Thus, the T300A polymorphism alters the function of motif-containing molecules that engage ATG16L1 through the WD40 domain, either by influencing this interaction under non-stressful conditions or by inhibiting their downstream autophagic signalling after caspase-mediated cleavage (Boada-Romero et al. 2016). Tethering ATG16L1 or LC3 induces targeted autophagic degradation of protein aggregates and mitochondria (Mei et al. 2023). The mammalian protein ATG16L1, primarily appreciated for its role in canonical autophagy and in noncanonical membrane atg8ylation processes, controls V-ATPase. An ATG16L1 knockout elevated V-ATPase activity, increased the V1 presence on endomembranes, and increased the number of acidified intracellular compartments (Duque et al. 2025).