F-box only protein 38 (FBXO38) is a member of the F-box family that mediates the ubiquitination and proteasome degradation of programmed death 1 (PD-1), and thus has important effects on T cell-related immunity. While its powerful role in adaptive immunity has attracted much attention, its regulatory roles in innate immune pathways remain unknown. The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is an important innate immune pathway that regulates type I interferons. STING protein is the core component of this pathway. In this study, we identified that FBXO38 deficiency enhanced tumor proliferation and reduced tumor CD8+ T cells infiltration. Loss of FBXO38 resulted in reduced STING protein levels in vitro and in vivo, further leading to preventing cGAS–STING pathway activation, and decreased downstream product IFNA1 and CCL5. The mechanism of reduced STING protein was associated with lysosome-mediated degradation rather than proteasomal function. Our results demonstrate a critical role for FBXO38 in the cGAS–STING pathway.

FBXO38

STING

IFNA1

CCL5

cGAS–STING pathway

cyclic GMP–AMP synthase–stimulator of interferon genes pathway

mature dendritic cells

differentially expressed genes

F-box only protein 38

Gene set enrichment analysis

interferon regulatory factor 3

Kyoto Encyclopedia of Genes and Genomes

Kruppel-like factor 7

lysosomal-associated membrane protein 1

programmed death-ligand 1

posttranslational modifications

SKP1-CUL1-F-box protein

tank-binding kinase 1

© 2024 The Authors. Published by Elsevier Inc.