The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-06-17 DOI:10.1016/j.celrep.2025.115870

Sabateeshan Mathavarajah, Sandhya Chipurupalli, Elias B Habib, William D Kim, Megan M Aoki, Dale P Corkery, Kennedy I T Whelan, Jordan Lukacs, Melis Erkan, Victor D Martinez, Kevin S Smith, Stephen B Montgomery, Jayme Salsman, Robert J Huber, Graham Dellaire

{"title":"The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy.","authors":"Sabateeshan Mathavarajah, Sandhya Chipurupalli, Elias B Habib, William D Kim, Megan M Aoki, Dale P Corkery, Kennedy I T Whelan, Jordan Lukacs, Melis Erkan, Victor D Martinez, Kevin S Smith, Stephen B Montgomery, Jayme Salsman, Robert J Huber, Graham Dellaire","doi":"10.1016/j.celrep.2025.115870","DOIUrl":null,"url":null,"abstract":"<p><p>The pre-mRNA processing factor 4 kinase (PRP4K) is an essential gene in animal cells, making interrogation of its function challenging. Here, we report characterization of a viable knockout model of PRP4K in the social amoeba Dictyostelium discoideum, revealing a function for PRP4K in splicing events controlling autophagy. When prp4k knockout amoebae undergo multicellular development, we observe defects in differentiation linked to abnormal autophagy and aberrant secretion of stalk cell inducer c-di-GMP. Autophagosome-lysosome fusion is impaired after PRP4K loss in both human cell lines and amoebae. PRP4K loss results in mis-splicing and reduced expression of the ESCRT-III gene CHMP4B in human cells and its ortholog vps32 in Dictyostelium, and re-expression of CHMP4B or Vps32 cDNA (respectively) restores normal autophagosome-lysosome fusion in PRP4K-deficient cells. Thus, our work reveals a PRP4K-CHMP4B/vps32 splicing circuit regulating autophagy that is conserved over at least 600 million years of evolution.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 7","pages":"115870"},"PeriodicalIF":7.5000,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.celrep.2025.115870","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

The pre-mRNA processing factor 4 kinase (PRP4K) is an essential gene in animal cells, making interrogation of its function challenging. Here, we report characterization of a viable knockout model of PRP4K in the social amoeba Dictyostelium discoideum, revealing a function for PRP4K in splicing events controlling autophagy. When prp4k knockout amoebae undergo multicellular development, we observe defects in differentiation linked to abnormal autophagy and aberrant secretion of stalk cell inducer c-di-GMP. Autophagosome-lysosome fusion is impaired after PRP4K loss in both human cell lines and amoebae. PRP4K loss results in mis-splicing and reduced expression of the ESCRT-III gene CHMP4B in human cells and its ortholog vps32 in Dictyostelium, and re-expression of CHMP4B or Vps32 cDNA (respectively) restores normal autophagosome-lysosome fusion in PRP4K-deficient cells. Thus, our work reveals a PRP4K-CHMP4B/vps32 splicing circuit regulating autophagy that is conserved over at least 600 million years of evolution.

查看原文本刊更多论文

进化上保守的PRP4K-CHMP4B/vps32剪接电路调节自噬。

前mrna加工因子4激酶（pre-mRNA processing factor 4 kinase, PRP4K）是动物细胞中的重要基因，对其功能的探究具有挑战性。在这里，我们报道了群居变形虫盘状盘齿龙（Dictyostelium disideum）中PRP4K基因敲除模型的特征，揭示了PRP4K基因在剪接事件中控制自噬的功能。当prp4k敲除变形虫进行多细胞发育时，我们观察到分化缺陷与异常自噬和柄细胞诱导剂c-di-GMP的异常分泌有关。在人类细胞系和变形虫中，PRP4K缺失后，自噬体-溶酶体融合受损。PRP4K缺失导致人类细胞中ESCRT-III基因CHMP4B及其同源基因vps32的错误剪接和表达减少，而在PRP4K缺失的细胞中，分别重新表达CHMP4B或vps32 cDNA可恢复正常的自噬体-溶酶体融合。因此，我们的工作揭示了PRP4K-CHMP4B/vps32剪接电路调节自噬，该电路在至少6亿年的进化中被保存下来。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.