Oncotarget

Research Papers:

The Bif-1-Dynamin 2 membrane fission machinery regulates Atg9-containing vesicle generation at the Rab11-positive reservoirs

Yoshinori Takahashi _, Nikolaos Tsotakos, Ying Liu, Megan M. Young, Jacob Serfass, Zhenyuan Tang, Thomas Abraham and Hong-Gang Wang

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Oncotarget. 2016; 7:20855-20868. https://doi.org/10.18632/oncotarget.8028

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Abstract

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

Correspondence to:

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

ABSTRACT

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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