ライ ショウホウ   RAI Shouho
  雷 小峰
   所属   埼玉医科大学  医学部 国際医療センター 皮膚科(皮膚腫瘍科)
   職種   助教
論文種別 学術雑誌(原著)
言語種別 英語
査読の有無 査読あり
表題 Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing
掲載誌名 正式名:JOURNAL OF CLINICAL INVESTIGATION
ISSNコード:0021-9738/1558-8238
出版社 AMER SOC CLINICAL INVESTIGATION INC
巻・号・頁 126(9),3417-3432頁
著者・共著者 Takuro Miyazaki,Kazuo Tonami,Shoji Hata,Toshihiro Aiuchi,Koji Ohnishi,Xiao-Feng Lei,Joo-ri Kim-Kaneyama,Motohiro Takeya,Hiroyuki Itabe,Hiroyuki Sorimachi,Hirold Kurihara,Akira Miyazaki
発行年月 2016/09
概要 Macrophages contribute to the development of atherosclerosis through pinocytotic deposition of native LDL-derived cholesterol in macrophages in the vascular wall. Inhibiting macrophage-mediated lipid deposition may have protective effects in atheroprone vasculature, and identifying mechanisms that potentiate this process may inform potential therapeutic interventions for atherosclerosis. Here, we report that dysregulation of exon junction complex-driven (EJC-driven) mRNA splicing confers hyperpinocytosis to macrophages during atherogenesis. Mechanistically, we determined that inflammatory cytoldnes induce an unconventional nonproteolytic calpain, calpain-6 (CAPN6), which associates with the essential EJC-loading factor CWC22 in the cytoplasm. This association disturbs the nuclear localization of CWC22, thereby suppressing the splicing of target genes, including those related to Rac1 signaling. CAPN6 deficiency in LDL receptor-deficient mice restored CWC22/EJC/Rac1 signaling, reduced pinocytotic deposition of native LDL in macrophages, and attenuated macrophage recruitment into the lesions, generating an atheroprotective phenotype in the aorta. In macrophages, the induction of CAPN6 in the atheroma interior limited macrophage movements, resulting in a decline in cell clearance from the lesions. Consistent with this finding, we observed that myeloid CAPN6 contributed to atherogenesis in a murine model of bone marrow transplantation. Furthermore, macrophages from advanced human atheromas exhibited increased CAPN6 induction and impaired CWC22 nuclear localization. Together, these results indicate that CAPN6 promotes atherogenicity in inflamed macrophages by disturbing CWC22/EJC systems.
DOI 10.1172/JCI85880
PMID 27525442