TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1
Jianwen Zhou, Nikoline Lander Rasmussen, Hallvard Lauritz Olsvik, Vyacheslav Akimov, Zehan Hu, Gry Evjen, Stéphanie Pébernard, Devanarayanan Siva Sankar, Carole Roubaty, Pauline Verlhac, Nicole van de Beek, Fulvio Reggiori, Yakubu Princely Abudu, Blagoy Blagoev, Trond Lamark, Terje Johansen, Jörn Dengjel
Abstract
Limitation of excessive inflammation due to selective degradation of pro-inflammatory proteins is one of the cytoprotective functions attributed to autophagy. In the current study, we highlight that selective autophagy also plays a vital role in promoting the establishment of a robust inflammatory response. Under inflammatory conditions, here TLR3-activation by poly(I:C) treatment, the inflammation repressor TNIP1 (TNFAIP3 interacting protein 1) is phosphorylated by Tank-binding kinase 1 (TBK1) activating an LIR motif that leads to the selective autophagy-dependent degradation of TNIP1, supporting the expression of pro-inflammatory genes and proteins. This selective autophagy efficiently reduces TNIP1 protein levels early (0-4 h) upon poly(I:C) treatment to allow efficient initiation of the inflammatory response. At 6 h, TNIP1 levels are restored due to increased transcription avoiding sustained inflammation. Thus, similarly as in cancer, autophagy may play a dual role in controlling inflammation depending on the exact state and timing of the inflammatory response.