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鲁帕他定抑制 OTUD3 通过去泛素化 MYL12A 和 PD-L1 促进弥漫性大 B 细胞淋巴瘤的进展和免疫逃逸。

Rupatadine-inhibited OTUD3 promotes DLBCL progression and immune evasion through deubiquitinating MYL12A and PD-L1.

机构信息

The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China.

出版信息

Cell Death Dis. 2024 Aug 3;15(8):561. doi: 10.1038/s41419-024-06941-x.

DOI:10.1038/s41419-024-06941-x
PMID:39097608
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11297949/
Abstract

The obstacle to effectively treating Diffuse Large B-cell Lymphoma (DLBCL) lies in the resistance observed toward standard therapies. Identifying therapeutic targets that prove effective for relapsed or refractory patients poses a significant challenge. OTUD3, a deubiquitinase enzyme, is overexpressed in DLBCL tissues. However, its role in DLBCL has not been investigated. Our study has brought to light the multifaceted impact of OTUD3 in DLBCL. Not only does it enhance cell survival through the deubiquitination of MYL12A, but it also induces CD8+ T cell exhaustion within the local environment by deubiquitinating PD-L1. Our findings indicate that the OTUD3 inhibitor, Rupatadine, exerts its influence through competitive binding with OTUD3. This operation diminishes the deubiquitination of both MYL12A and PD-L1 by OTUD3. This research unveils the central and oncogenic role of OTUD3 in DLBCL and highlights the potential clinical application value of the OTUD3 inhibitor, Rupatadine. These findings contribute valuable insights into addressing the challenges of resistant DLBCL cases and offer a promising avenue for further clinical exploration.

摘要

有效治疗弥漫性大 B 细胞淋巴瘤（DLBCL）的障碍在于对标准疗法的耐药性。确定对复发或难治性患者有效的治疗靶点是一个重大挑战。OTUD3 是一种去泛素化酶，在 DLBCL 组织中过表达。然而，其在 DLBCL 中的作用尚未得到研究。我们的研究揭示了 OTUD3 在 DLBCL 中的多方面影响。它不仅通过去泛素化 MYL12A 来增强细胞存活，还通过去泛素化 PD-L1 在局部环境中诱导 CD8+T 细胞耗竭。我们的发现表明，OTUD3 抑制剂 Rupatadine 通过与 OTUD3 的竞争性结合发挥作用。这种操作减少了 OTUD3 对 MYL12A 和 PD-L1 的去泛素化。这项研究揭示了 OTUD3 在 DLBCL 中的核心和致癌作用，并强调了 OTUD3 抑制剂 Rupatadine 的潜在临床应用价值。这些发现为解决耐药性 DLBCL 病例的挑战提供了有价值的见解，并为进一步的临床探索开辟了有前途的途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66f6/11297949/930b09e57126/41419_2024_6941_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66f6/11297949/930b09e57126/41419_2024_6941_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66f6/11297949/7651e49c3392/41419_2024_6941_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66f6/11297949/aa02ed37ad7c/41419_2024_6941_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66f6/11297949/10cd1517b8ec/41419_2024_6941_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66f6/11297949/add70c91bc57/41419_2024_6941_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66f6/11297949/a417ded61192/41419_2024_6941_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66f6/11297949/eab5c911f4e0/41419_2024_6941_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66f6/11297949/930b09e57126/41419_2024_6941_Fig8_HTML.jpg

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