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.
Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
Sanae
S
Shoji-Kawata
Rhea
R
Sumpter
Matthew
M
Leveno
Grant R
GR
Campbell
Zhongju
Z
Zou
Lisa
L
Kinch
Angela D
AD
Wilkins
Qihua
Q
Sun
Kathrin
K
Pallauf
Donna
D
MacDuff
Carlos
C
Huerta
Herbert W
HW
Virgin
J Bernd
JB
Helms
Ruud
R
Eerland
Sharon A
SA
Tooze
Ramnik
R
Xavier
Deborah J
DJ
Lenschow
Ai
A
Yamamoto
David
D
King
Olivier
O
Lichtarge
Nick V
NV
Grishin
Stephen A
SA
Spector
Dora V
DV
Kaloyanova
Beth
B
Levine
D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D002646:Chikungunya virus / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000166:cytology; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D014902:West Nile virus / Q000187:drug effects; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C458481:GLIPR2 protein, human; D008565:Membrane Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D054322:tat Gene Products, Human Immunodeficiency Virus