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鼠中脑啡肽原基因突变可抑制 B 细胞恶性肿瘤。

Viable mutations of mouse midnolin suppress B cell malignancies.

机构信息

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

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

出版信息

J Exp Med. 2024 Jun 3;221(6). doi: 10.1084/jem.20232132. Epub 2024 Apr 16.

DOI:10.1084/jem.20232132
PMID:38625151
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11022886/
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.

摘要

在一项遗传筛选中，我们鉴定出必需基因 Midnolin（Midn）的两个有活力的错义等位基因，这些等位基因与外周 B 细胞减少有关。在靶向敲除六个 MIDN 蛋白异构体中的四个的小鼠中，确认了因果关系。MIDN 主要在淋巴细胞中表达，在那里它增强蛋白酶体的活性。我们表明，纯化的 MIDN 在体外以依赖于泛素样结构域和 C 末端区域的方式直接刺激 26S 蛋白酶体的活性。MIDN 缺陷的 B 细胞显示出未折叠蛋白反应的 IRE-1/XBP-1 途径的异常激活。部分或完全的 MIDN 缺陷强烈抑制 Eμ-Myc 驱动的 B 细胞白血病和 Eμ-BCL2 对体内 B 细胞的抗凋亡作用，并诱导 Sp2/0 杂交瘤细胞在体外死亡，但仅部分损害正常淋巴细胞的发育。因此，MIDN 是支持正常淋巴发生的蛋白酶体活性所必需的，并且对于广泛的分化状态下的恶性 B 细胞增殖是必需的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/936d4f5a9a20/JEM_20232132_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/bdda68a708e5/JEM_20232132_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/4ea8d1b78b54/JEM_20232132_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/f3d19ea2d3c6/JEM_20232132_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/c2a073d5839d/JEM_20232132_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/683ff9ffc67c/JEM_20232132_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/94c014961dbc/JEM_20232132_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/38eeecca3a7b/JEM_20232132_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/fbc8deadb9ce/JEM_20232132_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/c171b7b5f867/JEM_20232132_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/29724ebac639/JEM_20232132_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/a4bcee9563a7/JEM_20232132_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/5046eb408157/JEM_20232132_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/936d4f5a9a20/JEM_20232132_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/bdda68a708e5/JEM_20232132_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/4ea8d1b78b54/JEM_20232132_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/f3d19ea2d3c6/JEM_20232132_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/c2a073d5839d/JEM_20232132_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/683ff9ffc67c/JEM_20232132_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/94c014961dbc/JEM_20232132_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/38eeecca3a7b/JEM_20232132_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/fbc8deadb9ce/JEM_20232132_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/c171b7b5f867/JEM_20232132_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/29724ebac639/JEM_20232132_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/a4bcee9563a7/JEM_20232132_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/5046eb408157/JEM_20232132_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f78/11022886/936d4f5a9a20/JEM_20232132_Fig8.jpg

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