Systematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis

Yesheng Fu, Lei Li, Xin Zhang, Zhikang Deng, Ying Wu, Wenzhe Chen, Yuchen Liu, Shan He, Jian Wang, Yuping Xie, Zhiwei Tu, Yadi Lyu, Yange Wei, Shujie Wang, Chun-Ping Cui, Cui Hua Liu () and Lingqiang Zhang ()
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Yesheng Fu: Beijing Institute of Lifeomics
Lei Li: Beijing Institute of Lifeomics
Xin Zhang: Beijing Institute of Lifeomics
Zhikang Deng: Beijing Institute of Lifeomics
Ying Wu: Beijing Institute of Lifeomics
Wenzhe Chen: Beijing Institute of Lifeomics
Yuchen Liu: Beijing Institute of Lifeomics
Shan He: Beijing Institute of Lifeomics
Jian Wang: Beijing Institute of Lifeomics
Yuping Xie: Beijing Institute of Lifeomics
Zhiwei Tu: Beijing Institute of Lifeomics
Yadi Lyu: Beijing Institute of Lifeomics
Yange Wei: Beijing Institute of Lifeomics
Shujie Wang: Beijing Institute of Lifeomics
Chun-Ping Cui: Beijing Institute of Lifeomics
Cui Hua Liu: Chinese Academy of Sciences
Lingqiang Zhang: Beijing Institute of Lifeomics

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Linear ubiquitination catalyzed by HOIL-1-interacting protein (HOIP), the key component of the linear ubiquitination assembly complex, plays fundamental roles in tissue homeostasis by executing domain-specific regulatory functions. However, a proteome-wide analysis of the domain-specific interactome of HOIP across tissues is lacking. Here, we present a comprehensive mass spectrometry-based interactome profiling of four HOIP domains in nine mouse tissues. The interaction dataset provides a high-quality HOIP interactome resource with an average of approximately 90 interactors for each bait per tissue. HOIP tissue interactome presents a systematic understanding of linear ubiquitination functions in each tissue and also shows associations of tissue functions to genetic diseases. HOIP domain interactome characterizes a set of previously undefined linear ubiquitinated substrates and elucidates the cross-talk among HOIP domains in physiological and pathological processes. Moreover, we show that linear ubiquitination of Integrin-linked protein kinase (ILK) decreases focal adhesion formation and promotes the detachment of Shigella flexneri-infected cells. Meanwhile, Hoip deficiency decreases the linear ubiquitination of Smad ubiquitination regulatory factor 1 (SMURF1) and enhances its E3 activity, finally causing a reduced bone mass phenotype in mice. Overall, our work expands the knowledge of HOIP-interacting proteins and provides a platform for further discovery of linear ubiquitination functions in tissue homeostasis.

Date: 2024
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DOI: 10.1038/s41467-024-47289-2

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