ATG8 and protein ATG8ylation - more than just Another TaG?

Since its discovery as a key component of the autophagosome membrane, the small ubiquitin-like protein ATG8 and its mammalian homologs (ATG8s) have garnered a lot of attention. Many researchers use it as a marker for autophagosome number, size and composition. A lot of research has focussed on its function in forming complexes required for autophagosome-lysosome fusion or generally, its interaction with other proteins via the ATG8-family interacting motif/AIM. Many additional functions have been discovered, for instance in non-canonical autophagy processes and in the nucleus. The list of known functions of ATG8 are ever expanding, and, most recently, evidence has emerged that, similar to ubiquitin, ATG8 can modify proteins by covalent attachment to a lysine residue (protein ATG8ylation). In this review, we aim to summarize the current literature on protein ATG8ylation and highlight the currently known substrates. We propose strategies to investigate this modification and provide an outlook for its possible cellular function.Abbreviations: ATG: autophagy related; DUBs: de-ubiquitinating enzymes; GABARAPL: GABA type A receptor associated protein like; GIR: GABARAP-interacting region; LIR: LC3-interacting region; MAP1LC3: microtubule associated protein 1 light chain 3; RMSD: root mean square; UBL: ubiquitin-like; UPS: ubiquitin-proteasome-system.