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肿瘤抑制因子 FBW7 的蛋白酶体降解需要 TRIP12 介导的分支泛素化。

Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12.

机构信息

Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK.

Hamad Bin Khalifa University, College of Health and Life Sciences Qatar Foundation, Education City, Education City, Doha, Qatar.

出版信息

Nat Commun. 2021 Apr 6;12(1):2043. doi: 10.1038/s41467-021-22319-5.

DOI:10.1038/s41467-021-22319-5
PMID:33824312
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8024278/
Abstract

The tumour suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), that targets several oncoproteins for proteasomal degradation. FBW7 is widely mutated and FBW7 protein levels are commonly downregulated in cancer. Here, using an shRNA library screen, we identify the HECT-domain E3 ubiquitin ligase TRIP12 as a negative regulator of FBW7 stability. We find that SCF-mediated ubiquitylation of FBW7 occurs preferentially on K404 and K412, but is not sufficient for its proteasomal degradation, and in addition requires TRIP12-mediated branched K11-linked ubiquitylation. TRIP12 inactivation causes FBW7 protein accumulation and increased proteasomal degradation of the SCF substrate Myeloid Leukemia 1 (MCL1), and sensitizes cancer cells to anti-tubulin chemotherapy. Concomitant FBW7 inactivation rescues the effects of TRIP12 deficiency, confirming FBW7 as an essential mediator of TRIP12 function. This work reveals an unexpected complexity of FBW7 ubiquitylation, and highlights branched ubiquitylation as an important signalling mechanism regulating protein stability.

摘要

肿瘤抑制因子 FBW7 是 E3 泛素连接酶复合物 SKP1-CUL1-F-box（SCF）的底物衔接蛋白，可将几种癌蛋白靶向到蛋白酶体进行降解。FBW7 广泛突变，并且在癌症中 FBW7 蛋白水平通常下调。在这里，我们使用 shRNA 文库筛选，鉴定出 HECT 结构域 E3 泛素连接酶 TRIP12 是 FBW7 稳定性的负调控因子。我们发现，SCF 介导的 FBW7 的泛素化优先发生在 K404 和 K412 上，但不足以使其进行蛋白酶体降解，并且还需要 TRIP12 介导的分支 K11 连接泛素化。TRIP12 的失活导致 FBW7 蛋白积累和 SCF 底物髓性白血病 1（MCL1）的蛋白酶体降解增加，并使癌细胞对抗微管化疗敏感。同时失活 FBW7 可挽救 TRIP12 缺乏的影响，证实 FBW7 是 TRIP12 功能的重要介质。这项工作揭示了 FBW7 泛素化的意外复杂性，并强调了分支泛素化作为调节蛋白质稳定性的重要信号机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/8bad43ab44b0/41467_2021_22319_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/bd9361b2e89c/41467_2021_22319_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/fefe86245066/41467_2021_22319_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/bc817df7e974/41467_2021_22319_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/6f9906ceb654/41467_2021_22319_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/bf327286f8b8/41467_2021_22319_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/4050180db0e8/41467_2021_22319_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/8bad43ab44b0/41467_2021_22319_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/bd9361b2e89c/41467_2021_22319_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/fefe86245066/41467_2021_22319_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/bc817df7e974/41467_2021_22319_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/6f9906ceb654/41467_2021_22319_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/bf327286f8b8/41467_2021_22319_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/4050180db0e8/41467_2021_22319_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0532/8024278/8bad43ab44b0/41467_2021_22319_Fig7_HTML.jpg

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