The core autophagy protein ATG9A controls dynamics of cell protrusions and directed migration

Abstract

Chemotactic migration is a fundamental cellular behavior relying on the coordinated flux of lipids and cargo proteins toward the leading edge. We found here that the core autophagy protein ATG9A plays a critical role in the chemotactic migration of several human cell lines, including highly invasive glioma cells. Depletion of ATG9A protein altered the formation of large and persistent filamentous actin (F-actin)–rich lamellipodia that normally drive directional migration. Using live-cell TIRF microscopy, we demonstrated that ATG9A-positive vesicles are targeted toward the migration front of polarized cells, where their exocytosis correlates with protrusive activity. Finally, we found that ATG9A was critical for efficient delivery of β1 integrin to the leading edge and normal adhesion dynamics. Collectively, our data uncover a new function for ATG9A protein and indicate that ATG9A-positive vesicles are mobilized during chemotactic stimulation to facilitate expansion of the lamellipodium and its anchorage to the extracellular matrix.

SHIP164 is a chorein motif lipid transfer protein that controls endosome–Golgi membrane traffic

“…Scramblases are expected to be functional partners of VPS13-ATG2 family members, as bulk transfer of lipids between cytosolic leaflets of adjacent bilayers requires scramblases to allow equilibration with the non-cytosolic leaflets ( Guardia et al, 2020 ; Matoba et al, 2020 ; Ghanbarpour et al, 2021 ). While ATG9A was discovered as a core component of the autophagy machinery, it is plausible that it may function in other contexts, as also recently reported ( Claude-Taupin et al, 2021 ; Mailler et al, 2021 ; Campisi et al, 2022 ). Interestingly, studies of ATG9A have consistently localized it to small vesicles often organized in clusters, similar to the SHIP164 vesicles described here ( Davies et al, 2018 ; Mari et al, 2010 ).…”

“…ATG2 was found to function in cooperation with the scramblase ATG9 to allow equilibration of delivered lipids between bilayer leaflets ( Guardia et al, 2020 ; Ghanbarpour et al, 2021 ; Matoba et al, 2020 ; Noda, 2021 ; Reinisch et al, 2021 ). In addition to its core role in autophagy, ATG9A also functions in other contexts ( Claude-Taupin et al, 2021 ; Mailler et al, 2021 ; Campisi et al, 2022 ), prompting us to explore whether, in addition to ATG2, it might also partner SHIP164. In WT cells, ATG9A is present in the Golgi complex area and also as scattered dots throughout the cytoplasm ( Fig.…”

ATG9A regulates dissociation of recycling endosomes from microtubules leading to formation of influenza A virus liquid condensates

“…This work highlights that ATG9A is a versatile component able to organize vesicular trafficking in ways that drive formation and activity of liquid condensates by limiting access to microtubules. This finding allocates a new function to the myriad of newly identified roles for ATG9A [26,34,35,46–49] beyond its well-known involvement in autophagy [30,33,37,50,51]. Recent studies support that ATG9A may be a key regulator of vesicular trafficking.…”

Nondegradable ubiquitinated ATG9A organizes Golgi integrity and dynamics upon stresses

“…A wealth of studies has shown that ATG9A is trafficked between the Golgi apparatus, plasma membrane, and endosomes to deliver lipids for autophagosome expansion and that it plays an essential role in providing a platform for autophagy initiation (Imai et al, 2016;Lamb et al, 2016;Mattera et al, 2017;Orsi et al, 2012;Popovic and Dikic, 2014;Puri et al, 2013;Soreng et al, 2018;Zhou et al, 2017). Recent reports indicate that ATG9A plays a role in the lipid transportation from lipid droplets to mitochondria and autophagosomes (Mailler et al, 2021) and regulates chemotactic migration through promoting the expansion of the lamellipodium (Campisi et al, 2022). Also, Deretic's laboratory shows that ATG9A functions in plasma membrane repair independent of its autophagy function (Claude-Taupin et al, 2021).…”