Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism PMID: 23954414

ADC Targets in Oncology

2026-04-10

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

Cell. 2013 Aug 29;154(5):1085-1099. doi: 10.1016/j.cell.2013.07.035.

Congcong He ¹ , Yongjie Wei ¹ , Kai Sun ² , Binghua Li ³ , Xiaonan Dong ⁴ , Zhongju Zou ¹ , Yang Liu ⁴ , Lisa N Kinch ⁵ , Shaheen Khan ³ , Sangita Sinha ⁶ , Ramnik J Xavier ⁷ , Nick V Grishin ⁵ , Guanghua Xiao ⁸ , Eeva-Liisa Eskelinen ⁹ , Philipp E Scherer ² , Jennifer L Whistler ¹⁰ , Beth Levine ¹¹

Affiliations

1. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2. Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4. Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6. Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58102, USA.
7. Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
8. Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
9. Department of Biosciences, Division of Biochemistry and Biotechnology, University of Helsinki, Helsinki, FI-00014 Finland.
10. Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, CA 94608, USA.
11. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].

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.