XBeclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism

Congcong He; Yongjie Wei; Kai Sun; Binghua Li; Xiaonan Dong; Zhongju Zou; Yang Liu; Lisa N. Kinch; Shaheen Khan; Sangita Sinha; Ramnik J. Xavier; Nick V. Grishin; Guanghua Xiao; Eeva Liisa Eskelinen; Philipp E. Scherer; Jennifer L. Whistler; Beth Levine

doi:10.1016/j.cell.2013.07.035

XBeclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism

Congcong He, Yongjie Wei, Kai Sun, Binghua Li, Xiaonan Dong, Zhongju Zou, Yang Liu, Lisa N. Kinch, Shaheen Khan, Sangita Sinha, Ramnik J. Xavier, Nick V. Grishin, Guanghua Xiao, Eeva Liisa Eskelinen, Philipp E. Scherer, Jennifer L. Whistler, Beth Levine^*

^*Corresponding author for this work

Cell & Developmental Biology

Research output: Contribution to journal › Article › peer-review

129 Scopus citations

Abstract

The molecular mechanism of autophagy and its relationship to other lysosomal degradation pathways remain incompletely understood. Here, we identified a previously uncharacterized mammalian-specific protein, Beclin 2, which, like Beclin 1, functions in autophagy and interacts with class III PI3K complex components and Bcl-2. However, Beclin 2, but not Beclin 1, functions in an additional lysosomal degradation pathway. Beclin 2 is required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) through its interaction with GASP1. Beclin 2 homozygous knockout mice have decreased embryonic viability, and heterozygous knockout mice have defective autophagy, increased levels of brain cannabinoid 1 receptor, elevated food intake, and obesity and insulin resistance. Our findings identify Beclin 2 as a converging regulator of autophagy and GPCR turnover and highlight the functional and mechanistic diversity of Beclin family members in autophagy, endolysosomal trafficking, and metabolism.

Original language	English (US)
Pages (from-to)	X1085-1099
Journal	Cell
Volume	154
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2013.07.035
State	Published - Aug 29 2013

Funding

We thank Haley Harrington for assistance with manuscript preparation and the Electron Microscopy Unit of the Institute of Biotechnology, University of Helsinki, Finland for providing laboratory facilities. This work was supported by NIH awards ROI CA109618 (B.L.), ROI GM094575 (N.V.G.), ROI DK55758 (P.E.S.), PO1 DK088761 (P.E.S.), ROI DA019958 (J.L.W.), ROI DK043351 (R.J.X.), K99 DK094980 (C.H.), R21 AI078198 (S.S.), and P20 RR015566 (S.S.); a Welch Foundation Award I-1505 (N.V.G.); and funds provided by the state of California for medical research on alcohol and substance abuse through the University of California, San Francisco to J.L.W. E.-L.E. was supported by the Academy of Finland. The authors Y.W., K.S., and B. Li all contributed equally to this manuscript.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2013.07.035

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He, C., Wei, Y., Sun, K., Li, B., Dong, X., Zou, Z., Liu, Y., Kinch, L. N., Khan, S., Sinha, S., Xavier, R. J., Grishin, N. V., Xiao, G., Eskelinen, E. L., Scherer, P. E., Whistler, J. L., & Levine, B. (2013). XBeclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. Cell, 154(5), X1085-1099. https://doi.org/10.1016/j.cell.2013.07.035

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title = "XBeclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism",

abstract = "The molecular mechanism of autophagy and its relationship to other lysosomal degradation pathways remain incompletely understood. Here, we identified a previously uncharacterized mammalian-specific protein, Beclin 2, which, like Beclin 1, functions in autophagy and interacts with class III PI3K complex components and Bcl-2. However, Beclin 2, but not Beclin 1, functions in an additional lysosomal degradation pathway. Beclin 2 is required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) through its interaction with GASP1. Beclin 2 homozygous knockout mice have decreased embryonic viability, and heterozygous knockout mice have defective autophagy, increased levels of brain cannabinoid 1 receptor, elevated food intake, and obesity and insulin resistance. Our findings identify Beclin 2 as a converging regulator of autophagy and GPCR turnover and highlight the functional and mechanistic diversity of Beclin family members in autophagy, endolysosomal trafficking, and metabolism.",

author = "Congcong He and Yongjie Wei and Kai Sun and Binghua Li and Xiaonan Dong and Zhongju Zou and Yang Liu and Kinch, {Lisa N.} and Shaheen Khan and Sangita Sinha and Xavier, {Ramnik J.} and Grishin, {Nick V.} and Guanghua Xiao and Eskelinen, {Eeva Liisa} and Scherer, {Philipp E.} and Whistler, {Jennifer L.} and Beth Levine",

note = "Funding Information: We thank Haley Harrington for assistance with manuscript preparation and the Electron Microscopy Unit of the Institute of Biotechnology, University of Helsinki, Finland for providing laboratory facilities. This work was supported by NIH awards ROI CA109618 (B.L.), ROI GM094575 (N.V.G.), ROI DK55758 (P.E.S.), PO1 DK088761 (P.E.S.), ROI DA019958 (J.L.W.), ROI DK043351 (R.J.X.), K99 DK094980 (C.H.), R21 AI078198 (S.S.), and P20 RR015566 (S.S.); a Welch Foundation Award I-1505 (N.V.G.); and funds provided by the state of California for medical research on alcohol and substance abuse through the University of California, San Francisco to J.L.W. E.-L.E. was supported by the Academy of Finland. The authors Y.W., K.S., and B. Li all contributed equally to this manuscript. ",

year = "2013",

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doi = "10.1016/j.cell.2013.07.035",

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T1 - XBeclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism

AU - He, Congcong

AU - Wei, Yongjie

AU - Sun, Kai

AU - Li, Binghua

AU - Dong, Xiaonan

AU - Zou, Zhongju

AU - Liu, Yang

AU - Kinch, Lisa N.

AU - Khan, Shaheen

AU - Sinha, Sangita

AU - Xavier, Ramnik J.

AU - Grishin, Nick V.

AU - Xiao, Guanghua

AU - Eskelinen, Eeva Liisa

AU - Scherer, Philipp E.

AU - Whistler, Jennifer L.

AU - Levine, Beth

N1 - Funding Information: We thank Haley Harrington for assistance with manuscript preparation and the Electron Microscopy Unit of the Institute of Biotechnology, University of Helsinki, Finland for providing laboratory facilities. This work was supported by NIH awards ROI CA109618 (B.L.), ROI GM094575 (N.V.G.), ROI DK55758 (P.E.S.), PO1 DK088761 (P.E.S.), ROI DA019958 (J.L.W.), ROI DK043351 (R.J.X.), K99 DK094980 (C.H.), R21 AI078198 (S.S.), and P20 RR015566 (S.S.); a Welch Foundation Award I-1505 (N.V.G.); and funds provided by the state of California for medical research on alcohol and substance abuse through the University of California, San Francisco to J.L.W. E.-L.E. was supported by the Academy of Finland. The authors Y.W., K.S., and B. Li all contributed equally to this manuscript.

PY - 2013/8/29

Y1 - 2013/8/29

N2 - The molecular mechanism of autophagy and its relationship to other lysosomal degradation pathways remain incompletely understood. Here, we identified a previously uncharacterized mammalian-specific protein, Beclin 2, which, like Beclin 1, functions in autophagy and interacts with class III PI3K complex components and Bcl-2. However, Beclin 2, but not Beclin 1, functions in an additional lysosomal degradation pathway. Beclin 2 is required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) through its interaction with GASP1. Beclin 2 homozygous knockout mice have decreased embryonic viability, and heterozygous knockout mice have defective autophagy, increased levels of brain cannabinoid 1 receptor, elevated food intake, and obesity and insulin resistance. Our findings identify Beclin 2 as a converging regulator of autophagy and GPCR turnover and highlight the functional and mechanistic diversity of Beclin family members in autophagy, endolysosomal trafficking, and metabolism.

AB - The molecular mechanism of autophagy and its relationship to other lysosomal degradation pathways remain incompletely understood. Here, we identified a previously uncharacterized mammalian-specific protein, Beclin 2, which, like Beclin 1, functions in autophagy and interacts with class III PI3K complex components and Bcl-2. However, Beclin 2, but not Beclin 1, functions in an additional lysosomal degradation pathway. Beclin 2 is required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) through its interaction with GASP1. Beclin 2 homozygous knockout mice have decreased embryonic viability, and heterozygous knockout mice have defective autophagy, increased levels of brain cannabinoid 1 receptor, elevated food intake, and obesity and insulin resistance. Our findings identify Beclin 2 as a converging regulator of autophagy and GPCR turnover and highlight the functional and mechanistic diversity of Beclin family members in autophagy, endolysosomal trafficking, and metabolism.

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VL - 154

SP - X1085-1099

JO - Cell

JF - Cell

IS - 5

ER -

XBeclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism

Abstract

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ASJC Scopus subject areas

UN SDGs

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