Journal article

HOIP Deficiency Causes Embryonic Lethality by Aberrant TNFR1-Mediated Endothelial Cell Death

Nieves Peltzer, Eva Rieser, Lucia Taraborrelli, Peter Draber, Maurice Darding, Barbara Pemaute, Yutaka Shimizu, Aida Sarr, Helena Draberova, Antonella Montinaro, Juan Pedro Martinez-Barbera, John Silke, Tristan A Rodriguez, Henning Walczak

Cell Reports | CELL PRESS | Published : 2014


Linear ubiquitination is crucial for innate and adaptive immunity. The linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP, and SHARPIN, is the only known ubiquitin ligase that generates linear ubiquitin linkages. HOIP is the catalytically active LUBAC component. Here, we show that both constitutive and Tie2-Cre-driven HOIP deletion lead to aberrant endothelial cell death, resulting in defective vascularization and embryonic lethality at midgestation. Ablation of tumor necrosis factor receptor 1 (TNFR1) prevents cell death, vascularization defects, and death at midgestation. HOIP-deficient cells are more sensitive to death induction by both tumor necrosis factor (TNF)..

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University of Melbourne Researchers


Awarded by Wellcome Trust Senior Investigator Award

Awarded by NHMRC

Awarded by Swiss National Science Foundation

Awarded by Medical Research Council

Awarded by Great Ormond Street Hospital Childrens Charity

Funding Acknowledgements

We thank Vishva Dixit and Domagoj Vucic from Genentech (South San Francisco, CA) for the linear-ubiquitin-specific antibody; Alessandro Annibaldi from The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research (London, UK) for helpful discussions; Aida Di Gregorio and Juan Miguel Sanchez Nieto at NHLI, Imperial College (London, UK) for technical assistance; Lorraine Lawrence at NHLI, Imperial College (London, UK) for histology services; and Arnold Pizzey at the UCL Cancer Institute (London, UK) for technical support with cell sorting experiments. This work was funded by a Wellcome Trust Senior Investigator Award (096831/Z/11/Z), a NHMRC grant awarded to J.S. and H.W. (602516) an ERC Advanced grant (294880) awarded to H.W., and a postdoctoral fellowship awarded to N.P. by the Swiss National Science Foundation (P2LAP3_148447).