The differential interactomes of the KRAS splice variants identify BIRC6 as a ubiquitin ligase for KRAS4A.

IF 6.9 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2025-01-28 Epub Date: 2024-12-19 DOI:10.1016/j.celrep.2024.115087

Juan Kochen Rossi, Cristina Nuevo-Tapioles, Rachel A O'Keefe, Moritz Hunkeler, Anna M Schmoker, Mercedes Fissore-O'Leary, Wenjuan Su, Ian M Ahearn, Cristina Branco, Hakyung Cheong, Dominic Esposito, Ioana Clotea, Beatrix Ueberheide, Eric S Fischer, Mark R Philips

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Abstract

Transcripts of the KRAS locus are alternatively spliced to generate two proteins, KRAS4A and KRAS4B, which differ in their membrane-targeting sequences. These splice variants have been conserved for more than 450 million years, suggesting non-overlapping functions driven by differential membrane association. Here, we use proximity labeling to map the differential interactomes of the KRAS splice variants. We find 24 and 10 proteins that interact specifically with KRAS4A or KRAS4B, respectively. The KRAS interacting protein most specific to KRAS4A is BIRC6, a large member of the inhibitor of apoptosis protein family unique in possessing E2/E3 ubiquitin ligase activity. We find that this interaction takes place on the Golgi apparatus and results in the mono- and di-ubiquitination of KRAS4A at lysines 128 and 147. Silencing BIRC6 diminishes GTP loading of and growth stimulation by KRAS4A but not KRAS4B. Thus, BIRC6 is a ubiquitin ligase that inhibits apoptosis and also modifies KRAS4A.

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KRAS剪接变体的差异相互作用组鉴定BIRC6是KRAS4A的泛素连接酶。

KRAS 基因座的转录本通过交替剪接产生两种蛋白质 KRAS4A 和 KRAS4B，它们的膜靶序列不同。这些剪接变体已经保存了 4.5 亿多年，表明它们在不同膜关联的驱动下具有非重叠功能。在这里，我们使用近似标记技术绘制了 KRAS 剪接变体的不同相互作用组图。我们发现分别有 24 个和 10 个蛋白质与 KRAS4A 或 KRAS4B 有特异性相互作用。与 KRAS4A 最特异的 KRAS 相互作用蛋白是 BIRC6，它是凋亡抑制蛋白家族的一个大型成员，具有 E2/E3 泛素连接酶活性。我们发现，这种相互作用发生在高尔基体上，并导致 KRAS4A 在赖氨酸 128 和 147 处发生单泛素化和双泛素化。沉默 BIRC6 会降低 KRAS4A 的 GTP 负载和生长刺激，但不会降低 KRAS4B 的 GTP 负载和生长刺激。因此，BIRC6 是一种泛素连接酶，它能抑制细胞凋亡，也能修饰 KRAS4A。

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 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.