STING-driven activation of TFEB/TFE3 establishes a negative feedback loop to control immune homeostasis

Yuyuan Wang; Yu Luo; Fei Zhou; Dan Li

doi:10.1016/j.cellsig.2025.112322

STING-driven activation of TFEB/TFE3 establishes a negative feedback loop to control immune homeostasis

Cell Signal. 2026 Mar:139:112322. doi: 10.1016/j.cellsig.2025.112322. Epub 2025 Dec 12.

Authors

Yuyuan Wang¹, Yu Luo¹, Fei Zhou¹, Dan Li²

Affiliations

¹ Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China.
² Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China; Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University Avenue, Ann Arbor, MI 48109, USA. Electronic address: lidan@zjut.edu.cn.

PMID: 41391678
DOI: 10.1016/j.cellsig.2025.112322

Abstract

Recently several studies have identified that transcription factor EB (TFEB) and transcription factor E3 (TFE3) are the crucial regulators bridging the crosstalk between lysosomes and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Moreover, this TFEB/TFE3-mediated pathway establishes an essential negative feedback loop, revealing a novel self-regulatory mechanism in innate immunity, which suppresses IRF3 phosphorylation and IFN secretion, reduces caspase-3 activation, and enhances cell survival. Collectively, these findings unveil a critical role for TFEB/TFE3 in the maintenance of immune homeostasis, highlighting their functions in preventing excessive immune responses and protecting cell survival. In this review, we will summarize these findings and discuss the new insights they bring to our understanding of the interplay among the cGAS-STING pathway, lysosomal function, and innate immunity.

Keywords: Autophagy; Lysosomes; TFE3; TFEB; cGAS-STING.

Publication types

Review

MeSH terms

Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors* / metabolism
Feedback, Physiological
Homeostasis*
Humans
Immunity, Innate*
Interferon Regulatory Factor-3 / metabolism
Lysosomes / metabolism
Membrane Proteins* / metabolism
STING Protein
Signal Transduction

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Membrane Proteins
STING1 protein, human
TFEB protein, human
TFE3 protein, human
Interferon Regulatory Factor-3
STING Protein