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FBXO11 constitutes a major negative regulator of MHC class II through ubiquitin- dependent proteasomal degradation of CIITA

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Title: FBXO11 constitutes a major negative regulator of MHC class II through ubiquitin- dependent proteasomal degradation of CIITA
Authors: Kasuga, Yusuke Browse this author
Ouda, Ryota Browse this author
Watanabe, Masashi Browse this author
Sun, Xin Browse this author
Kimura, Miki Browse this author
Hatakeyama, Shigetsugu Browse this author →KAKEN DB
Kobayashi, Koichi S. Browse this author
Keywords: FBXO11
Issue Date: 13-Jun-2023
Publisher: National Academy of Sciences.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America (PNAS)
Volume: 120
Issue: 24
Start Page: e2218955120
Publisher DOI: 10.1073/pnas.2218955120
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 part-ner 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 ubiq-uitin-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.
Type: article
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 小林 弘一

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