Traf6 and A20 Regulate Lysine 63-Linked Ubiquitination of Beclin 1 Controlling TLR4-Induced Autophagy

摘要

Autophagy delivers cytoplasmic constituents to autolysosomes and has been linked to both innate and adaptive immunity. Toll-Like Receptor 4 (TLR4) signaling induces autophagy and recruits Beclin 1 to the receptor complex. Here we show that Traf6-mediated lysine (K) 63-linked ubiquitination of Beclin 1 is critical for TLR4 triggered autophagy in macrophages. Two Traf6 binding motifs in Beclin 1 facilitated Traf6 binding and its ubiquitination. Beclin 1 K117, strategically located in the Beclin 1 BH3 domain is a major site for K63-linked ubiquitination. A20, a known deubiquitinating enzyme, reduced Beclin 1 K63-linked ubiquitination, and limited the induction of autophagy following TLR signaling. Treatment of macrophages with either interferon-γ or IL-1 also triggered K63-linked ubiquitination of Beclin 1 and autophagosome formation. These results indicate that the status of Beclin 1 K63-linked ubiquitination plays a key role in regulating autophagy during inflammatory responses.