The RNF8/OPTN/KDM6A axis controls macrophage polarization to maintain testicular microenvironment homeostasis.

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-07-24 DOI:10.1038/s41420-025-02641-3

Yanan Guo, Peng Xia, Yixiao Tian, Daosen Fu, Xiaohui Hu, Kun Xie, Wenhao Dong, Wei Zhang, Disheng Liu, Rong Shen, Degui Wang

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引用次数: 0

Abstract

Dysregulated immune responses may erroneously target normal reproductive tissues, thereby compromising the proper functioning of the reproductive system. Macrophages are the most abundant immune cells in the testes, however, the role of macrophages in spermatogenic function is not yet clear. This study indicated that the increase of pro-inflammatory macrophages impaired the development of spermatogenic cells, and the deficiency of RNF8 led to a proinflammatory state in the testicular microenvironment and diminished sperm production in mice. RNF8 mainly assembled K63-branched ubiquitin chains on autophagy receptor OPTN at K448 thus causing OPTN activation. The increased ubiquitination of OPTN promoted degradation of KDM6A via the autophagy-lysosome pathway, thereby inhibiting macrophage polarization towards the pro-inflammatory type and maintaining an immune privilege state in the testicular microenvironment. This homeostasis could be collapsed once the RNF8-OPTN-KDM6A axis was abnormal, subsequently resulting in remodeling of the testicular microenvironment. This study reveals the underlying mechanism of RNF8 on male reproduction, and the pro-inflammatory microenvironment resulting from RNF8 deficiency hindered spermatogenic cell differentiation, thereby impairing spermatogenic function.

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RNF8/OPTN/KDM6A轴控制巨噬细胞极化维持睾丸微环境稳态。

失调的免疫反应可能错误地针对正常的生殖组织，从而损害生殖系统的正常功能。巨噬细胞是睾丸中最丰富的免疫细胞，但巨噬细胞在生精功能中的作用尚不清楚。本研究表明，促炎巨噬细胞的增加损害了生精细胞的发育，RNF8的缺乏导致小鼠睾丸微环境的促炎状态和精子产生减少。RNF8主要将k63分支的泛素链组装在自噬受体OPTN的K448上，从而引起OPTN活化。OPTN泛素化的增加通过自噬-溶酶体途径促进KDM6A的降解，从而抑制巨噬细胞向促炎型极化，维持睾丸微环境中的免疫特权状态。一旦RNF8-OPTN-KDM6A轴异常，这种内稳态就会被破坏，随后导致睾丸微环境的重塑。本研究揭示了RNF8影响男性生殖的潜在机制，RNF8缺乏导致的促炎微环境阻碍了生精细胞的分化，从而损害了生精功能。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.