Endogenous HMGB1 regulates autophagy

Daolin Tang, Rui Kang, Kristen M. Livesey, Chun Wei Cheh, Adam Farkas, Patricia Loughran, George Hoppe, Marco E. Bianchi, Kevin J. Tracey, Herbert J. Zeh, Michael T. Lotze

Research output: Contribution to journalArticle

524 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)881-892
Number of pages12
JournalJournal of Cell Biology
Volume190
Issue number5
DOIs
StatePublished - Sep 6 2010

ASJC Scopus subject areas

  • Cell Biology

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    Tang, D., Kang, R., Livesey, K. M., Cheh, C. W., Farkas, A., Loughran, P., Hoppe, G., Bianchi, M. E., Tracey, K. J., Zeh, H. J., & Lotze, M. T. (2010). Endogenous HMGB1 regulates autophagy. Journal of Cell Biology, 190(5), 881-892. https://doi.org/10.1083/jcb.200911078