一项全基因组筛选通过 RNF146 和 TNKS/2 将过氧物酶体调控与 Wnt 信号传导联系起来。

IF 7.4 1区 生物学 Q1 CELL BIOLOGY
Journal of Cell Biology Pub Date : 2024-10-07 Epub Date: 2024-07-05 DOI:10.1083/jcb.202312069
Jonathan T Vu, Katherine U Tavasoli, Connor J Sheedy, Soham P Chowdhury, Lori Mandjikian, Julien Bacal, Meghan A Morrissey, Chris D Richardson, Brooke M Gardner
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引用次数: 0

摘要

过氧物酶体是一种膜结合细胞器,内含代谢酶。人类的正常发育需要过氧物酶体,但调节过氧物酶体功能的基因仍不清楚。我们进行了全基因组 CRISPRi 筛选,以鉴定参与过氧物酶体稳态的新因子。我们发现,抑制 RNF146(一种由聚(ADP-核糖)激活的 E3 连接酶)会减少蛋白质向过氧化物酶体的输入。RNF146 介导的过氧化物酶体导入损失取决于多(ADP-核糖)聚合酶 TNKS 和 TNKS2 的稳定和活性,而 TNKS2 与过氧化物酶体膜蛋白 PEX14 结合。我们认为,RNF146 和 TNKS/2 通过过氧化物酶体膜上蛋白的 PARsylation 来调节过氧化物酶体的导入效率。有趣的是,我们发现过氧化物酶体的缺失增加了 TNKS/2 和 RNF146 对非过氧化物酶体底物的依赖性降解,包括 β-catenin破坏复合体成分 AXIN1,这足以改变 β-catenin转录的幅度。这些观察结果表明,RNF146不仅在过氧化物酶体调控中发挥了以前未曾描述过的作用,而且在发育过程中还在连接过氧化物酶体功能与Wnt/β-catenin信号方面发挥了新的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A genome-wide screen links peroxisome regulation with Wnt signaling through RNF146 and TNKS/2.

Peroxisomes are membrane-bound organelles harboring metabolic enzymes. In humans, peroxisomes are required for normal development, yet the genes regulating peroxisome function remain unclear. We performed a genome-wide CRISPRi screen to identify novel factors involved in peroxisomal homeostasis. We found that inhibition of RNF146, an E3 ligase activated by poly(ADP-ribose), reduced the import of proteins into peroxisomes. RNF146-mediated loss of peroxisome import depended on the stabilization and activity of the poly(ADP-ribose) polymerases TNKS and TNKS2, which bind the peroxisomal membrane protein PEX14. We propose that RNF146 and TNKS/2 regulate peroxisome import efficiency by PARsylation of proteins at the peroxisome membrane. Interestingly, we found that the loss of peroxisomes increased TNKS/2 and RNF146-dependent degradation of non-peroxisomal substrates, including the β-catenin destruction complex component AXIN1, which was sufficient to alter the amplitude of β-catenin transcription. Together, these observations not only suggest previously undescribed roles for RNF146 in peroxisomal regulation but also a novel role in bridging peroxisome function with Wnt/β-catenin signaling during development.

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来源期刊
Journal of Cell Biology
Journal of Cell Biology 生物-细胞生物学
CiteScore
12.60
自引率
2.60%
发文量
213
审稿时长
1 months
期刊介绍: The Journal of Cell Biology (JCB) is a comprehensive journal dedicated to publishing original discoveries across all realms of cell biology. We invite papers presenting novel cellular or molecular advancements in various domains of basic cell biology, along with applied cell biology research in diverse systems such as immunology, neurobiology, metabolism, virology, developmental biology, and plant biology. We enthusiastically welcome submissions showcasing significant findings of interest to cell biologists, irrespective of the experimental approach.
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