최진혁 (University of Texas Southwestern Medical Center)

한빛사논문

조회192

University of Texas Southwestern Medical Center

J. Exp. Med., April 16 2024 | https://doi.org/10.1084/jem.20232132 Viable mutations of mouse midnolin suppress B cell malignancies

Xue Zhong ¹, Nagesh Peddada¹, James J Moresco ¹, Jianhui Wang ¹, Yiao Jiang ¹, Jonathan J Rios ^2,3,4,5, Eva Marie Y. Moresco ¹, Jin Huk Choi ¹, Bruce Beutler ¹

¹Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center , Dallas, TX, USA.

²Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children , Dallas, TX, USA.

³McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center , Dallas, TX, USA.

⁴Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

⁵Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Correspondence to Bruce Beutler, Jin Huk Choi

Abstract

In a genetic screen, we identified two viable missense alleles of the essential gene Midnolin (Midn) that were associated with reductions in peripheral B cells. Causation was confirmed in mice with targeted deletion of four of six MIDN protein isoforms. MIDN was expressed predominantly in lymphocytes where it augmented proteasome activity. We showed that purified MIDN directly stimulated 26S proteasome activity in vitro in a manner dependent on the ubiquitin-like domain and a C-terminal region. MIDN-deficient B cells displayed aberrant activation of the IRE-1/XBP-1 pathway of the unfolded protein response. Partial or complete MIDN deficiency strongly suppressed Eμ-Myc-driven B cell leukemia and the antiapoptotic effects of Eμ-BCL2 on B cells in vivo and induced death of Sp2/0 hybridoma cells in vitro, but only partially impaired normal lymphocyte development. Thus, MIDN is required for proteasome activity in support of normal lymphopoiesis and is essential for malignant B cell proliferation over a broad range of differentiation states.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-17)
연구진국외 연구진
분야

댓글 작성 로그인

CV 열람하기

연락처 보기