Endogenous HMGB1 regulates autophagy

Journal of Cell Biology - Tập 190 Số 5 - Trang 881-892 - 2010
Daolin Tang1, Rui Kang1, Kristen M. Livesey1, Chun-Wei Cheh1, Adam M. Farkas1, Patricia Loughran1, George Hoppe2, Marco E. Bianchi3, Kevin J. Tracey4,5, Wei‐Guo Zhu1, Michael T. Lotze1
1Damage Associated Molecular Pattern Molecule Laboratory, Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15219 1
2Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195 2
3Department of Genetics and Cell Biology, San Raffaele University and Research Institute, 20132 Milano, Italy 3
4Feinstein Institute for Medical Research, Manhasset, NY 11030 4
5North Shore Long Island Jewish Health System

Tóm tắt

Autophagy clears long-lived proteins and dysfunctional organelles and generates substrates for adenosine triphosphate production during periods of starvation and other types of cellular stress. Here we show that high mobility group box 1 (HMGB1), a chromatin-associated nuclear protein and extracellular damage-associated molecular pattern molecule, is a critical regulator of autophagy. Stimuli that enhance reactive oxygen species promote cytosolic translocation of HMGB1 and thereby enhance autophagic flux. HMGB1 directly interacts with the autophagy protein Beclin1 displacing Bcl-2. Mutation of cysteine 106 (C106), but not the vicinal C23 and C45, of HMGB1 promotes cytosolic localization and sustained autophagy. Pharmacological inhibition of HMGB1 cytoplasmic translocation by agents such as ethyl pyruvate limits starvation-induced autophagy. Moreover, the intramolecular disulfide bridge (C23/45) of HMGB1 is required for binding to Beclin1 and sustaining autophagy. Thus, endogenous HMGB1 is a critical pro-autophagic protein that enhances cell survival and limits programmed apoptotic cell death.

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Thông tin xuất bản

Journal of Cell Biology

Tập 190 Số 5

881-892

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