Proximity proteomics reveals role of Abelson interactor 1 in the regulation of TAK1/RIPK1 signaling,Molecular Oncology

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Proximity proteomics reveals role of Abelson interactor 1 in the regulation of TAK1/RIPK1 signaling
Molecular Oncology ( IF 5.0 ) Pub Date : 2023-01-12 , DOI: 10.1002/1878-0261.13374
Max Petersen _{1,

2,

3} , Anna Chorzalska _{1,

2} , Makayla Pardo _{1,

2} , Anaelena Rodriguez _{1,

2} , John Morgan ₄ , Nagib Ahsan _{5,

6,

7} , Ting C Zhao ₈ , Olin Liang _{1,

2,

9} , Leszek Kotula _{10,

11,

12} , Paul Bertone _{1,

2,

9} , Philip A Gruppuso ₁₃ , Patrycja M Dubielecka _{1,

2,

3,

9}

Affiliation

Department of Medicine, Alpert Medical School, Brown University, Providence, RI, USA.
Division of Hematology/Oncology, Rhode Island Hospital, Providence, RI, USA.
Division of Biology and Medicine, Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.
Flow Cytometry and Cell Sorting Core Facility, Roger Williams Medical Center, Providence, RI, USA.
COBRE Center for Cancer Research Development, Proteomics Core Facility, Rhode Island Hospital, Providence, RI, USA.
Department of Chemistry and Biochemistry, The University of Oklahoma, Norman, OK, USA.
Mass Spectrometry, Proteomics and Metabolomics Core Facility, Stephenson Life Sciences Research Center, The University of Oklahoma, Norman, OK, USA.
Department of Surgery, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA.
Legorreta Cancer Center, Alpert Medical School, Brown University, Providence, RI, USA.
Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.
Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA.
Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.
Division of Pediatric Endocrinology, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA.

Dysregulation of the adaptor protein Abelson interactor 1 (ABI1) is linked to malignant transformation. To interrogate the role of ABI1 in cancer development, we mapped the ABI1 interactome using proximity-dependent labeling (PDL) with biotin followed by mass spectrometry. Using a novel PDL data filtering strategy, considering both peptide spectral matches and peak areas of detected peptides, we identified 212 ABI1 proximal interactors. These included WAVE2 complex components such as CYFIP1, NCKAP1, or WASF1, confirming the known role of ABI1 in the regulation of actin-polymerization-dependent processes. We also identified proteins associated with the TAK1-IKK pathway, including TAK1, TAB2, and RIPK1, denoting a newly identified function of ABI1 in TAK1-NF-κB inflammatory signaling. Functional assays using TNFα-stimulated, ABI1-overexpressing or ABI1-deficient cells showed effects on the TAK1-NF-kB pathway-dependent signaling to RIPK1, with ABI1-knockout cells being less susceptible to TNFα-induced, RIPK1-mediated, TAK1-dependent apoptosis. In sum, our PDL-based strategy enabled mapping of the ABI1 proximal interactome, thus revealing a previously unknown role of this adaptor protein in TAK1/RIPK1-based regulation of cell death and survival.

中文翻译：

邻近蛋白质组学揭示了 Abelson 相互作用子 1 在 TAK1/RIPK1 信号传导调节中的作用

接头蛋白 Abelson 相互作用蛋白 1 (ABI1) 的失调与恶性转化有关。为了探究 ABI1 在癌症发展中的作用，我们使用生物素邻近依赖性标记 (PDL) 和质谱分析绘制了 ABI1 相互作用组。使用新颖的 PDL 数据过滤策略，考虑肽光谱匹配和检测到的肽的峰面积，我们鉴定了 212 个 ABI1 近端相互作用因子。其中包括 WAVE2 复杂组件，如 CYFIP1、NCKAP1 或 WASF1，证实了 ABI1 在调节肌动蛋白聚合依赖过程中的已知作用。我们还鉴定了与 TAK1-IKK 通路相关的蛋白质，包括 TAK1、TAB2 和 RIPK1，表明 ABI1 在 TAK1-NF-κB 炎症信号传导中新发现的功能。使用 TNFα 刺激、 ABI1过表达或ABI1缺陷细胞进行的功能测定显示，TAK1-NF-kB 通路依赖性 RIPK1 信号传导受到影响， ABI1敲除细胞对 TNFα 诱导、RIPK1 介导、TAK1- 不太敏感。依赖性细胞凋亡。总之，我们基于 PDL 的策略能够绘制 ABI1 近端相互作用组图谱，从而揭示了该接头蛋白在基于 TAK1/RIPK1 的细胞死亡和存活调节中的先前未知的作用。

更新日期：2023-01-12

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