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Sci. Signal., 25 May 2010
Vol. 3, Issue 123, p. ra42
[DOI: 10.1126/scisignal.2000751]

RESEARCH ARTICLES

TRAF6 and A20 Regulate Lysine 63–Linked Ubiquitination of Beclin-1 to Control TLR4-Induced Autophagy

Chong-Shan Shi* and John H. Kehrl*

B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Abstract: Autophagy delivers cytoplasmic constituents to autophagolysosomes and is linked to both innate and adaptive immunity. Toll-like receptor 4 (TLR4) signaling induces autophagy and recruits Beclin-1, the mammalian homolog of yeast Atg6, to the receptor complex. We found that tumor necrosis factor receptor (TNFR)–associated factor 6 (TRAF6)–mediated, Lys63 (K63)–linked ubiquitination of Beclin-1 is critical for TLR4-triggered autophagy in macrophages. Two TRAF6-binding motifs in Beclin-1 facilitated the binding of TRAF6 and the ubiquitination of Beclin-1. Lys117, which is strategically located in the Bcl-2 homology 3 (BH3) domain of Beclin-1, was a major site for K63-linked ubiquitination. The deubiquitinating enzyme A20 reduced the extent of K63-linked ubiquitination of Beclin-1 and limited the induction of autophagy in response to TLR signaling. Treatment of macrophages with either interferon-{gamma} or interleukin-1 also triggered the K63-linked ubiquitination of Beclin-1 and the formation of autophagosomes. These results indicate that the status of K63-linked ubiquitination of Beclin-1 plays a key role in regulating autophagy during inflammatory responses.

* To whom correspondence should be addressed. E-mail: cshi{at}niaid.nih.gov (C.-S.S.); jkehrl{at}niaid.nih.gov (J.H.K.)

Citation: C. S. Shi, J. H. Kehrl, TRAF6 and A20 Regulate Lysine 63–Linked Ubiquitination of Beclin-1 to Control TLR4-Induced Autophagy. Sci. Signal. 3, ra42 (2010).

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