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去泛素化酶 OTUD1 调节多发性骨髓瘤中的免疫球蛋白产生和蛋白酶体抑制剂敏感性。

The deubiquitinase OTUD1 regulates immunoglobulin production and proteasome inhibitor sensitivity in multiple myeloma.

机构信息

Department of Hematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Syllabova 19, 703 00, Czech Republic.

Department of Hematooncology, University Hospital Ostrava, Ostrava, 17. listopadu 1790/5, 708 00, Czech Republic.

出版信息

Nat Commun. 2022 Nov 10;13(1):6820. doi: 10.1038/s41467-022-34654-2.

DOI:10.1038/s41467-022-34654-2
PMID:36357400
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9649770/
Abstract

Serum monoclonal immunoglobulin (Ig) is the main diagnostic factor for patients with multiple myeloma (MM), however its prognostic potential remains unclear. On a large MM patient cohort (n = 4146), we observe no correlation between serum Ig levels and patient survival, while amount of intracellular Ig has a strong predictive effect. Focused CRISPR screen, transcriptional and proteomic analysis identify deubiquitinase OTUD1 as a critical mediator of Ig synthesis, proteasome inhibitor sensitivity and tumor burden in MM. Mechanistically, OTUD1 deubiquitinates peroxiredoxin 4 (PRDX4), protecting it from endoplasmic reticulum (ER)-associated degradation. In turn, PRDX4 facilitates Ig production which coincides with the accumulation of unfolded proteins and higher ER stress. The elevated load on proteasome ultimately potentiates myeloma response to proteasome inhibitors providing a window for a rational therapy. Collectively, our findings support the significance of the Ig production machinery as a biomarker and target in the combinatory treatment of MM patients.

摘要

血清单克隆免疫球蛋白 (Ig) 是多发性骨髓瘤 (MM) 患者的主要诊断因素，但其预后潜力尚不清楚。在一项大型 MM 患者队列 (n=4146) 中，我们观察到血清 Ig 水平与患者生存之间没有相关性，而细胞内 Ig 的含量具有很强的预测作用。聚焦的 CRISPR 筛选、转录组和蛋白质组分析确定去泛素化酶 OTUD1 是 Ig 合成、蛋白酶体抑制剂敏感性和 MM 肿瘤负担的关键介质。从机制上讲，OTUD1 去泛素化过氧化物酶 4 (PRDX4)，使其免受内质网 (ER) 相关降解。反过来，PRDX4 促进 Ig 的产生，这与未折叠蛋白的积累和更高的 ER 应激相一致。蛋白酶体的负担增加最终增强了骨髓瘤对蛋白酶体抑制剂的反应，为合理的治疗提供了一个窗口。总的来说，我们的研究结果支持 Ig 产生机制作为 MM 患者联合治疗的生物标志物和靶点的重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/fbf7f611052a/41467_2022_34654_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/8580dca4d132/41467_2022_34654_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/40454d6f1963/41467_2022_34654_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/250c38777da1/41467_2022_34654_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/55c9d2a1edf8/41467_2022_34654_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/9eef81c2f9cc/41467_2022_34654_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/2b5efd76e69a/41467_2022_34654_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/45844c3fa48c/41467_2022_34654_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/fbf7f611052a/41467_2022_34654_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/8580dca4d132/41467_2022_34654_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/40454d6f1963/41467_2022_34654_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/250c38777da1/41467_2022_34654_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/55c9d2a1edf8/41467_2022_34654_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/9eef81c2f9cc/41467_2022_34654_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/2b5efd76e69a/41467_2022_34654_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/45844c3fa48c/41467_2022_34654_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d1e/9649770/fbf7f611052a/41467_2022_34654_Fig8_HTML.jpg

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