Work in Anne Simonsen’s group is focusing on understanding the role of membrane-binding proteins in autophagy, a process that is crucial for cellular homeostasis. Here, Alf Håkon Lystad and colleagues have identified two membrane-binding regions in the core autophagy protein ATG16L1 that are important for the function of the protein in membrane conjugation of LC3 and GABARAP proteins during autophagy.
In collaboration with Sven Carlsson at Umeå university and Thomas Melia at Yale university they show that an N-terminal amphipathic helix in ATG16L1 directly affects lipidation of LC3 and GABARAP and is required for all types of autophagy. The second membrane-binding region is located in the b-isoform specific region of the C-terminal part of ATG16L1. The ATG16L1 C-terminus corresponds to a ~400 amino acid expansion acquired in its evolution from yeast to man and is dispensable for starvation-induced canonical autophagy. This extension, found in metazoans in general, thus provides novel functions of ATG16L1 in autophagy-related processes that are yet poorly understood. Lystad and co-workers now show that the b-isoform specific membrane-binding region of ATG16L1 is important for conjugation of LC3 and GABARAP to perturbed single layered endo-lysosomal membranes. Interestingly, this autophagy-related process is independent of ULK and VPS34 protein complexes that are required for conventional autophagy. Further studies are needed to elucidate possible pathophysiological implications of these results, but the identification of isoform-specific roles of ATG16L1 provides additional means to distinguish between conventional and non-conventional autophagy-related functions of ATG16L1.
Links:
The NCB journal article:
Distinct functions of ATG16L1 isoforms in membrane binding and LC3B lipidation in autophagy-related processes.
Alf Håkon Lystad, Sven R. Carlsson, Laura R. de la Ballina, Karlina J. Kauffman, Shanta Nag, Tamotsu Yoshimori, Thomas J. Melia & Anne Simonsen
Nat Cell Biol 21, 372-383, doi:10.1038/s41556-019-0274-9 (2019).