ATG proteins are essential to autophagy, most notably in mediating autophagosome formation. ATG9A and ATG9B are the only transmembrane ATG proteins, and have been shown to display scramblase activity, capable of moving lipids between the bilayer. This function is thought to occur in tandem with ATG2A and/or ATG2B, which are lipid transfer proteins. Recent studies, however, have suggested additional functions of ATG9A outside of autophagy. To investigate this further, Sharon Tooze and colleagues use mass spectrometry and immunoprecipitation experiments to identify novel interactors of ATG9A. In this Short Report (van Vliet et al., 2024), the authors identify a number of lipid metabolic proteins, of particular interest are VPS13A and VPS13C. Interestingly, these proteins belong to the same family as ATG2A. By assessing interactions of ATG9A with four fragments of VPS13A, the authors show that like ATG2A, ATG9A can bind to VPS13A via its C-terminus. Using AlphaFold structure predictions, they map the binding site in this region. Unexpectedly, however, the N-terminal fragment of VPS13A also retains its ability to interact with ATG9A, suggesting that it may also assist in binding. Functionally, an ATG2A–VPS13A chimera (with the ATG2A C-terminus swapped for the VPS13A C-terminus) was unable to restore autophagic flux in cells lacking ATG2A and ATG2B. Thus, this study not only identifies novel interactors of ATG9A, but also provides insights into potential functions of the ATG9A–VPS13A complex outside of autophagy.
