Identification of a candidate therapeutic autophagy-inducing peptide

Shoji-Kawata S., et al. Nature, 2013. 494(7436): p. 201-206.

Speaker: Pei-Chi Chen (陳佩琪)                                           Time: 15:00~16:00, May 8, 2013

Commentator: Dr. Chung-Hsin Tseng (曾忠信 老師)         Location: Room 601

Abstract:

Autophagy is a lysosomal degradation pathway that maintains the cytoplasm homeostasis by eliminating aggregated proteins and damaged organelles. It is known that autophagy protects against diverse neurodegenerative disorders, microbial infections, cancer and metabolic diseases. In this study, Shoji-Kawata et al manipulated a cell-permeable peptide that induces autophagy and that has the potential to defend against various disease-causing agents. Originally, HIV-1 virulence factor Nef readily bind to beclin 1 in consequence blocking autophagic maturation. By mapping the Nef-interacting domain of beclin 1, they found amino acids 267-284 in the ECD were the essential residues that interacted with Nef. Using this 18 amino-acid residues as a template, they designed the fusion peptide—Tat-beclin 1 which is essential and sufficient for inducing autophagy. Furthermore, the authors reported a novel negative regulator of autophagy—GAPR-1 which interacts with both endogenous beclin 1 and Tat-beclin 1. Normally, GAPR-1 imprisons beclin 1 in the Golgi to inhibit its autophagic properties, however after delivering Tat-beclin 1, it competes with and releasesbeclin 1 from Golgi, leading to the formation of autophagosomes. The peptide derivative had the potential of decreasing viral loads of several RNA virus infections including SINV, CHIKV, WNV and HIV-1, and eliminating intracellular bacterium, L. monocytogenes in vitro. It also showed improvement in the clinical outcome and mortality of in vivo neonatal mice infected with CHIKV and WNV. In addition, the peptide assists in clearance of soluble or small polyglutamine expansion protein aggregates associated with the neurodegenerative disorder in vitro. Due to its specificautophagy-induction property, the Tat-beclin 1 peptide may possess potential of prevention and treatment of a broad range of diseases.

References:

1.         Rubinsztein, D.C., P. Codogno, and B. Levine, Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov, 2012. 11(9): p. 709-30.