Identification of a candidate therapeutic autophagy-inducing peptide



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.

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Figure 1: Tat–beclin 1 peptide induces autophagy in vitro.
Figure 2: Tat–beclin 1 peptide binds to GAPR-1, a beclin 1-interacting protein.
Figure 3: Tat–beclin 1 peptide decreases aggregates of a polyglutamine expansion protein and has anti-infective activity.
Figure 4: Tat–beclin 1 peptide induces autophagy and exerts antiviral activity in vivo.


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We thank M. Diamond, J. L. Foster, M. Gale, N. Mizushima, D. Sabatini, M. Shiloh and T. Yoshimori for supplying critical reagents; and H. Ball, A. Bugde and E.-L. Eskelinen for assistance with peptide synthesis, infrared imaging and EM interpretation, respectively. This work was supported by NIH grants U54AI057156 (B.L.), K08 AI099150 (R.S.), ROI NS077874 (S.A.S), RO1 GM094575 (N.V.G.), ROI GM066099 (O.L.), ROI GM079656 (O.L.), ROI NS063973 (A.Y.), ROI NS050199 (A.Y.), U54AI057160 (H.W.V., D.J.L.), ROI DK083756 (R.X.), ROI DK086502 (R.X.), and T32 GM008297 (C.H.); NSF CCF-0905536 (O.L.); an NWO-ALW Open Program Grant 817.02.023 (J.B.H.); Cancer Research UK (S.A.T.); and a Welch Foundation Award I-15-5 (N.V.G.).

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B.L., S.S.-K. and O.L. generated the original hypothesis. S.S.-K., R.S., M.L., G.R.C., Z.Z., Q.S., K.P., D.M., C.H., R.E., D.K. and D.V.K. performed experiments. L.K., A.D.W., R.X., O.L. and N.V.G. performed bioinformatics analyses. B.L., S.S.-K., R.S., M.L., L.K., H.W.V., J.B.H., S.A.T., R.X., D.J.L., A.Y., O.L., N.V.G., S.A.S. and D.V.K. provided intellectual contributions throughout the project. B.L., S.S.-K. and R.S. took primary responsibility for writing the manuscript. All authors edited the manuscript.

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Correspondence to Beth Levine.

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This file contains Supplementary Figures 1-28 and Supplementary Table 1. This file was replaced on 13 February 2013 as the original had corrupted. (PDF 2373 kb)

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Shoji-Kawata, S., Sumpter, R., Leveno, M. et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201–206 (2013).

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