TY - JOUR
T1 - The dynamin Vps1 mediates Atg9 transport to the sites of autophagosome formation
AU - Arlt, Henning
AU - Raman, Babu
AU - Filali-Mouncef, Yasmina
AU - Hu, Yan
AU - Leytens, Alexandre
AU - Hardenberg, Ralph
AU - Guimarães, Rodrigo
AU - Kriegenburg, Franziska
AU - Mari, Muriel
AU - Smaczynska-de Rooij, Iwona I
AU - Ayscough, Kathryn R
AU - Dengjel, Jörn
AU - Ungermann, Christian
AU - Reggiori, Fulvio
PY - 2023/5
Y1 - 2023/5
N2 - Autophagy is a key process in eukaryotes to maintain cellular homeostasis by delivering cellular components to lysosomes/vacuoles for degradation and reuse of the resulting metabolites. Membrane rearrangements and trafficking events are mediated by the core machinery of autophagy-related (Atg) proteins, which carry out a variety of functions. How Atg9, a lipid scramblase and the only conserved transmembrane protein within this core Atg machinery, is trafficked during autophagy remained largely unclear. Here, we addressed this question in yeast Saccharomyces cerevisiae and found that retromer complex and dynamin Vps1 mutants alter Atg9 subcellular distribution and severely impair the autophagic flux by affecting two separate autophagy steps. We provide evidence that Vps1 interacts with Atg9 at Atg9 reservoirs. In the absence of Vps1, Atg9 fails to reach the sites of autophagosome formation, and this results in an autophagy defect. The function of Vps1 in autophagy requires its GTPase activity. Moreover, Vps1 point mutants associated with human diseases such as microcytic anemia and Charcot-Marie-Tooth are unable to sustain autophagy and affect Atg9 trafficking. Together, our data provide novel insights on the role of dynamins in Atg9 trafficking and suggest that a defect in this autophagy step could contribute to severe human pathologies.
AB - Autophagy is a key process in eukaryotes to maintain cellular homeostasis by delivering cellular components to lysosomes/vacuoles for degradation and reuse of the resulting metabolites. Membrane rearrangements and trafficking events are mediated by the core machinery of autophagy-related (Atg) proteins, which carry out a variety of functions. How Atg9, a lipid scramblase and the only conserved transmembrane protein within this core Atg machinery, is trafficked during autophagy remained largely unclear. Here, we addressed this question in yeast Saccharomyces cerevisiae and found that retromer complex and dynamin Vps1 mutants alter Atg9 subcellular distribution and severely impair the autophagic flux by affecting two separate autophagy steps. We provide evidence that Vps1 interacts with Atg9 at Atg9 reservoirs. In the absence of Vps1, Atg9 fails to reach the sites of autophagosome formation, and this results in an autophagy defect. The function of Vps1 in autophagy requires its GTPase activity. Moreover, Vps1 point mutants associated with human diseases such as microcytic anemia and Charcot-Marie-Tooth are unable to sustain autophagy and affect Atg9 trafficking. Together, our data provide novel insights on the role of dynamins in Atg9 trafficking and suggest that a defect in this autophagy step could contribute to severe human pathologies.
KW - PAS
KW - SNX
KW - atg9
KW - autophagosome
KW - autophagy
KW - dynamin
KW - phagophore
KW - retromer
KW - sorting nexin
KW - vps1
UR - http://www.scopus.com/inward/record.url?scp=85157963997&partnerID=8YFLogxK
U2 - 10.1016/j.jbc.2023.104712
DO - 10.1016/j.jbc.2023.104712
M3 - Journal article
C2 - 37060997
SN - 0021-9258
VL - 299
JO - The Journal of Biological Chemistry
JF - The Journal of Biological Chemistry
IS - 5
M1 - 104712
ER -