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

Kasuga, Yusuke; Ouda, Ryota; Watanabe, Masashi; Sun, Xin; Kimura, Miki; Hatakeyama, Shigetsugu; Kobayashi, Koichi S.

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

Kasuga, Yusuke; Ouda, Ryota; Watanabe, Masashi et al.

Proceedings of the National Academy of Sciences of the United States of America (PNAS), 2023, 120(24), e2218955120

Permalink : https://hdl.handle.net/2115/90949

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アクセス権	open access
URI	https://hdl.handle.net/2115/90949
タイトル	FBXO11 constitutes a major negative regulator of MHC class II through ubiquitin- dependent proteasomal degradation of CIITA
著者	Kasuga, Yusuke ; Ouda, Ryota ; Watanabe, Masashi ; Sun, Xin ; Kimura, Miki ; Hatakeyama, Shigetsugu ; Kobayashi, Koichi S.
著者名 Kasuga, Yusuke
著者名 Ouda, Ryota
著者名 Watanabe, Masashi
著者名 Sun, Xin
著者名 Kimura, Miki
e-Rad_Researcher 70294973 著者名 Hatakeyama, Shigetsugu
著者名 Kobayashi, Koichi S.
言語	英語
キーワード	FBXO11
	MHC-II
	CIITA
	ubiquitination
	NLRC5
発行日	2023-06-13
出版者	National Academy of Sciences.
収録物名	Proceedings of the National Academy of Sciences of the United States of America (PNAS)
巻(号)	120(24)
ページ	e2218955120
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Version of Record
権利情報	Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
PISSN	0027-8424
関連情報 (isIdenticalTo)	出版社版DOI https://doi.org/10.1073/pnas.2218955120