Identification of a candidate therapeutic autophagy-inducing peptide

Sanae Shoji-Kawata, Rhea Sumpter, Matthew Leveno, Grant R. Campbell, Zhongju Zou, Lisa Kinch, Angela D. Wilkins, Qihua Sun, Kathrin Pallauf, Donna MacDuff, Carlos Huerta, Herbert W. Virgin, J. Bernd Helms, Ruud Eerland, Sharon A. Tooze, Ramnik Xavier, Deborah J. Lenschow, Ai Yamamoto, David King, Olivier Lichtarge, Nick V. Grishin, Stephen A. Spector, Dora V. Kaloyanova and Beth Levine ()
Additional contact information
Sanae Shoji-Kawata: UT Southwestern Medical Center
Rhea Sumpter: UT Southwestern Medical Center
Matthew Leveno: UT Southwestern Medical Center
Grant R. Campbell: University of California, San Diego, La Jolla, California 92093, USA
Zhongju Zou: UT Southwestern Medical Center
Lisa Kinch: Howard Hughes Medical Institute, UT Southwestern Medical Center
Angela D. Wilkins: Baylor College of Medicine
Qihua Sun: UT Southwestern Medical Center
Kathrin Pallauf: UT Southwestern Medical Center
Donna MacDuff: Washington University School of Medicine
Carlos Huerta: UT Southwestern Medical Center
Herbert W. Virgin: Washington University School of Medicine
J. Bernd Helms: Utrecht University, Utrecht 3508TD, The Netherlands
Ruud Eerland: Utrecht University, Utrecht 3508TD, The Netherlands
Sharon A. Tooze: London Research Institute, Cancer Research UK, London EC1V 4AD, UK
Ramnik Xavier: Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School
Deborah J. Lenschow: Washington University School of Medicine
Ai Yamamoto: Columbia University College of Physicians & Surgeons
David King: Howard Hughes Medical Institute, University of California
Olivier Lichtarge: Baylor College of Medicine
Nick V. Grishin: Howard Hughes Medical Institute, UT Southwestern Medical Center
Stephen A. Spector: University of California, San Diego, La Jolla, California 92093, USA
Dora V. Kaloyanova: Utrecht University, Utrecht 3508TD, The Netherlands
Beth Levine: UT Southwestern Medical Center

Nature, 2013, vol. 494, issue 7436, 201-206

Abstract: Abstract The lysosomal degradation pathway of autophagy has a crucial role in defence against infection, neurodegenerative disorders, cancer and ageing. Accordingly, agents that induce autophagy may have broad therapeutic applications. One approach to developing such agents is to exploit autophagy manipulation strategies used by microbial virulence factors. Here we show that a peptide, Tat–beclin 1—derived from a region of the autophagy protein, beclin 1, which binds human immunodeficiency virus (HIV)-1 Nef—is a potent inducer of autophagy, and interacts with a newly identified negative regulator of autophagy, GAPR-1 (also called GLIPR2). Tat–beclin 1 decreases the accumulation of polyglutamine expansion protein aggregates and the replication of several pathogens (including HIV-1) in vitro, and reduces mortality in mice infected with chikungunya or West Nile virus. Thus, through the characterization of a domain of beclin 1 that interacts with HIV-1 Nef, we have developed an autophagy-inducing peptide that has potential efficacy in the treatment of human diseases.

Date: 2013
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DOI: 10.1038/nature11866

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