A TBK1-independent primordial function of STING in lysosomal biogenesis.

Autor:	Lv B; Aging Institute, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA 15219, USA; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA., Dion WA; Aging Institute, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA 15219, USA., Yang H; Aging Institute, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA 15219, USA; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA., Xun J; Aging Institute, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA 15219, USA; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA., Kim DH; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA., Zhu B; Aging Institute, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA 15219, USA; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA., Tan JX; Aging Institute, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA 15219, USA; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA. Electronic address: jay.tan@pitt.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 Oct 17; Vol. 84 (20), pp. 3979-3996.e9. Date of Electronic Publication: 2024 Sep 19.
DOI:	10.1016/j.molcel.2024.08.026
Abstrakt:	Stimulator of interferon genes (STING) is activated in many pathophysiological conditions, leading to TBK1-dependent interferon production in higher organisms. However, primordial functions of STING independent of TBK1 are poorly understood. Here, through proteomics and bioinformatics approaches, we identify lysosomal biogenesis as an unexpected function of STING. Transcription factor EB (TFEB), an evolutionarily conserved regulator of lysosomal biogenesis and host defense, is activated by STING from multiple species, including humans, mice, and frogs. STING-mediated TFEB activation is independent of TBK1, but it requires STING trafficking and its conserved proton channel. GABARAP lipidation, stimulated by the channel of STING, is key for STING-dependent TFEB activation. STING stimulates global upregulation of TFEB-target genes, mediating lysosomal biogenesis and autophagy. TFEB supports cell survival during chronic sterile STING activation, a common condition in aging and age-related diseases. These results reveal a primordial function of STING in the biogenesis of lysosomes, essential organelles in immunity and cellular stress resistance. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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