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体内筛选表明内切核糖核酸酶 Regnase-1 参与调节衰老相关溶酶体变化。

In-vivo screening implicates endoribonuclease Regnase-1 in modulating senescence-associated lysosomal changes.

机构信息

Laboratory of Extracellular Matrix Regeneration, Institute of Translational Medicine, Department of Health Sciences and Technology, ETH Zürich, CH-8603, Schwerzenbach, Switzerland.

European Institute for the Biology of Aging (ERIBA)/University Medical Center Groningen (UMCG), Groningen, The Netherlands.

出版信息

Geroscience. 2024 Apr;46(2):1499-1514. doi: 10.1007/s11357-023-00909-z. Epub 2023 Aug 29.

DOI:10.1007/s11357-023-00909-z
PMID:37644339
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10828269/
Abstract

Accumulation of senescent cells accelerates aging and age-related diseases, whereas preventing this accumulation extends the lifespan in mice. A characteristic of senescent cells is increased staining with β-galactosidase (β-gal) ex vivo. Here, we describe a progressive accumulation of β-gal staining in the model organism C. elegans during aging. We show that distinct pharmacological and genetic interventions targeting the mitochondria and the mTORC1 to the nuclear core complex axis, the non-canonical apoptotic, and lysosomal-autophagy pathways slow the age-dependent accumulation of β-gal. We identify a novel gene, rege-1/Regnase-1/ZC3H12A/MCPIP1, modulating β-gal staining via the transcription factor ets-4/SPDEF. We demonstrate that knocking down Regnase-1 in human cell culture prevents senescence-associated β-gal accumulation. Our data provide a screening pipeline to identify genes and drugs modulating senescence-associated lysosomal phenotypes.

摘要

衰老细胞的积累加速了衰老和与年龄相关的疾病，而防止这种积累可以延长小鼠的寿命。衰老细胞的一个特征是β-半乳糖苷酶（β-gal）染色增加。在这里，我们描述了在衰老过程中模式生物秀丽隐杆线虫中β-gal 染色的逐渐积累。我们表明，针对线粒体和 mTORC1 到核核心复合物轴、非经典凋亡和溶酶体自噬途径的不同药理学和遗传学干预措施，可减缓β-gal 随年龄的积累。我们鉴定了一个新基因 rege-1/Regnase-1/ZC3H12A/MCPIP1，通过转录因子 ets-4/SPDEF 调节β-gal 染色。我们证明在人细胞培养物中敲低 Regnase-1 可防止与衰老相关的β-gal 积累。我们的数据提供了一个筛选管道，可用于鉴定调节与衰老相关的溶酶体表型的基因和药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1577/10828269/c7f55c243617/11357_2023_909_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1577/10828269/682814b8c642/11357_2023_909_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1577/10828269/787f390d9f4b/11357_2023_909_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1577/10828269/ace16ed98f91/11357_2023_909_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1577/10828269/c7f55c243617/11357_2023_909_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1577/10828269/682814b8c642/11357_2023_909_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1577/10828269/787f390d9f4b/11357_2023_909_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1577/10828269/ace16ed98f91/11357_2023_909_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1577/10828269/c7f55c243617/11357_2023_909_Fig4_HTML.jpg

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