Editors' ChoiceCell Biology

Fighting Disease with Autophagy

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Sci. Signal.  19 Feb 2013:
Vol. 6, Issue 263, pp. ec45
DOI: 10.1126/scisignal.2004078

Autophagy is a degradative process through which cells survive periods of nutrient scarcity or dispose of defective proteins or organelles. The removal of viruses and other pathogens by autophagy is an important aspect of the immune response, and some viruses, including HIV-1, evade elimination by inhibiting autophagy (see commentary by García-Sastre). Noting that the HIV-1 protein Nef binds to and inhibits the autophagy protein beclin 1, Shoji-Kawata et al. used immunoprecipitation assays to identify an 18–amino acid residue region of beclin 1 that was required for this physical association. The authors linked this sequence to the protein transduction domain of the HIV-1 protein Tat to generate the cell-permeable peptide Tat–beclin 1. Compared to a Tat-linked scrambled peptide (Tat-scrambled), the Tat–beclin 1 peptide induced autophagy in various cell lines through a canonical mechanism that required components downstream of beclin 1. Biochemical and mass spectrometry analyses revealed that Tat–beclin 1, but not Tat-scrambled, was a binding partner for Golgi-associated plant pathogenesis–related protein 1 (GAPR-1). Knockdown of GAPR-1 in HeLa cells led to enhanced basal autophagosome formation in the absence of Tat–beclin 1, suggesting that GAPR-1 is an endogenous inhibitor of autophagy. Microscopic analysis showed that endogenous beclin 1 was sequestered to the Golgi by GAPR-1; however, in the presence of the Tat–beclin 1 peptide, beclin 1 redistributed to the cytoplasm. Pretreatment of cells with Tat–beclin 1, but not Tat-scrambled, before infection with various viruses, including HIV-1 and West Nile virus (WNV), led to decreased viral replication. In addition, Tat–beclin 1, but not Tat-scrambled, reduced the amounts of protein aggregates in a cellular model of huntingtin protein accumulation. Immunohistochemical analysis showed that Tat–beclin 1 induced autophagy in mice without toxic effects. Finally, administration of Tat–beclin 1 to mice infected with WNV or chikungunya virus led to decreased viral replication and increased survival. Together, these data identify GAPR-1 as an endogenous inhibitor of autophagy and suggest that peptide-mediated induction of autophagy may have therapeutic benefit in various human diseases.

S. Shoji-Kawata, R. Sumpter Jr., M. Leveno, G. R. Campbell, Z. Zou, L. Kinch, A. D. Wilkins, Q. Sun, K. Pallauf, D. Macduff, C. Huerta, H. W. Virgin, J. B. Helms, R. Eerland, S. A. Tooze, R. Xavier, D. J. Lenschow, A. Yamamoto, D. King, O. Lichtarge, N. V. Grishin, S. A. Spector, D. V. Kaloyanova, B. Levine, Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201–206 (2013). [PubMed]

A. García-Sastre, Beneficial lessons from viruses. Nature 494, 181–182 (2013). [PubMed]