The Bif-1-Dynamin 2 membrane fission machinery regulates Atg9-containing vesicle generation at the Rab11-positive reservoirs
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Yoshinori Takahashi1,4,*, Nikolaos Tsotakos1,*, Ying Liu2, Megan M. Young1, Jacob Serfass2, Zhenyuan Tang2, Thomas Abraham3, Hong-Gang Wang1,2,4
1Department of Pediatrics, Penn State University College of Medicine, Hershey, PA 17033, USA
2Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA
3Department of Neural and Behavioral Science and the Microscopy Imaging Facility, Penn State University College of Medicine, Hershey, PA 17033, USA
4Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033, USA
*These authors contributed equally to this work
Yoshinori Takahashi, e-mail: [email protected]
Hong-Gang Wang, e-mail: [email protected]
Keywords: autophagy, Atg9 vesicle, Bif-1, Dynamin 2, Rab11-positive reservoir
Received: October 12, 2015 Accepted: February 15, 2016 Published: March 10, 2016
Atg9 is a multispanning transmembrane protein that is required for autophagosome formation. During autophagy, vesicles containing Atg9 are generated through an unknown mechanism and delivered to the autophagosome formation sites. We have previously reported that Atg9-containing membranes undergo continuous tubulation and fission during nutrient starvation in a manner dependent on the curvature-inducing protein Bif-1/Sh3glb1. Here, we identify Dynamin 2 (DNM2) as a Bif-1-interacting protein that mediates the fission of Atg9-containing membranes during autophagy. The interaction of Bif-1 and DNM2 is enhanced upon nutrient starvation, and Bif-1 and DNM2 cooperatively induce the generation of Atg9-containing vesicles. Inhibition of the GTPase activity of DNM2 results in the accumulation of Atg9-positive tubular structures that originate from a Rab11-positive reservoir. Although Atg9 seems to be constitutively trafficked to the reservoir regardless of Bif-1 expression, membrane tubulation from the Atg9 reservoir is dependent on Bif-1 and is strongly induced upon nutrient starvation. These findings suggest that the generation of Atg9 vesicles from a Rab11-positive reservoir is tightly controlled by the Bif-1-DNM2 membrane fission machinery in response to cellular demand for autophagy.
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