RRC ID 75817
Author Kasuga Y, Ouda R, Watanabe M, Sun X, Kimura M, Hatakeyama S, Kobayashi KS.
Title FBXO11 constitutes a major negative regulator of MHC class II through ubiquitin-dependent proteasomal degradation of CIITA.
Journal Proc Natl Acad Sci U S A
Abstract Major histocompatibility complex (MHC) class I and II molecules play critical roles in the activation and regulation of adaptive immunity through antigen presentation to CD8+ and CD4+ T cells, respectively. Strict regulation of MHC expression is critical for proper immune responses. CIITA (MHC class II transactivator), an NLR (nucleotide-binding domain, leucine-rich-repeat containing) protein, is a master regulator of MHC class II (MHC-II) gene transcription. Although it has been known that CIITA activity is regulated at the transcriptional and protein levels, the mechanism to determine CIITA protein level has not been elucidated. Here, we show that FBXO11 is a bona fide E3 ligase of CIITA and regulates CIITA protein level through ubiquitination-mediated degradation. A nonbiased proteomic approach for CIITA-binding protein identified FBXO11, a member of the Skp1-Cullin-1-F-box E3 ligase complex, as a binding partner of CIITA but not MHC class I transactivator, NLRC5. The cycloheximide chase assay showed that the half-life of CIITA is mainly regulated by FBXO11 via the ubiquitin-proteasome system. The expression of FBXO11 led to the reduced MHC-II at the promoter activity level, transcriptional level, and surface expression level through downregulation of CIITA. Moreover, human and mouse FBXO11-deficient cells display increased levels of MHC-II and related genes. In normal and cancer tissues, FBXO11 expression level is negatively correlated with MHC-II. Interestingly, the expression of FBXO11, along with CIITA, is associated with prognosis of cancer patients. Therefore, FBXO11 is a critical regulator to determine the level of MHC-II, and its expression may serve as a biomarker for cancer.
Volume 120(24)
Pages e2218955120
Published 2023-6-13
DOI 10.1073/pnas.2218955120
PMID 37279268
MeSH Animals F-Box Proteins* / genetics Genes, MHC Class II HLA Antigens Histocompatibility Antigens Class I / genetics Histocompatibility Antigens Class I / metabolism Histocompatibility Antigens Class II / genetics Histocompatibility Antigens Class II / metabolism Humans Intracellular Signaling Peptides and Proteins / metabolism Mice Neoplasms* / genetics Protein-Arginine N-Methyltransferases / genetics Protein-Arginine N-Methyltransferases / metabolism Proteomics Trans-Activators / metabolism Ubiquitin / metabolism Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism
IF 9.412
Human and Animal Cells 293T(RCB2202)