Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency.

Abstract

The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.

• Authors: Hirotsugu Oda, Kalpana Manthiram, Pallavi Pimpale Chavan, Eva Rieser, Önay Veli, Öykü Kaya, Charles Rauch, Shuichiro Nakabo, Hye Sun Kuehn, Mariël Swart, Yanli Wang, Nisa Ilgim Çelik, Anne Molitor, Vahid Ziaee, Nasim Movahedi, Mohammad Shahrooei, Nima Parvaneh, Nasrin Alipour-Olyei, Raphael Carapito, Qin Xu, Silvia Preite, David B Beck, Jae Jin Chae, Michele Nehrebecky, Amanda K Ombrello, Patrycja Hoffmann, Tina Romeo, Natalie T Deuitch, Brynja Matthíasardóttir, James Mullikin, Hirsh Komarow, Jennifer Stoddard, Julie Niemela, Kerry Dobbs, Colin L Sweeney, Holly Anderton, Kate E Lawlor, Hiroyuki Yoshitomi, Dan Yang, Manfred Boehm, Jeremy Davis, Pamela Mudd, Davide Randazzo, Wanxia Li Tsai, Massimo Gadina, Mariana J Kaplan, Junya Toguchida, Christian T Mayer, Sergio D Rosenzweig, Luigi D Notarangelo, Kazuhiro Iwai, John Silke, Pamela L Schwartzberg, Bertrand Boisson, Jean-Laurent Casanova, Seiamak Bahram, Anand Prahalad Rao, Nieves Peltzer, Henning Walczak, Najoua Lalaoui, Ivona Aksentijevich, Daniel L Kastner
• Journal: Nature immunology (Nat Immunol) Vol. 25 Issue 5 Pg. 764-777 (May 2024) ISSN: 1529-2916 [Electronic] United States
• PMID: 38609546 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Case Reports)
• Copyright: © 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Chemical References

• SHARPIN protein, human
• NF-kappa B
• Ubiquitin-Protein Ligases
• Intracellular Signaling Peptides and Proteins
• sharpin
• Nerve Tissue Proteins
• Ubiquitins

Topics

• Humans
• Immunologic Deficiency Syndromes (genetics, immunology)
• Female
• Male
• NF-kappa B (metabolism)
• Ubiquitin-Protein Ligases (genetics)
• Inflammation (immunology, genetics)
• B-Lymphocytes (immunology)
• Loss of Function Mutation
• Fibroblasts (metabolism, immunology)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Animals
• Mice
• Alleles
• Nerve Tissue Proteins
• Ubiquitins