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 SCRs 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 Wire Condiment Caddies 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.