Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death

Rosalind L. Ang, Mark Chan, Diana Legarda, John P. Sundberg, Shao Cong Sun, Virginia L. Gillespie, Nicholas Chun, Peter S. Heeger, Huabao Xiong, Sergio A. Lira, Adrian T. Ting

Research output: Contribution to journalArticlepeer-review

Abstract

SHARPIN, together with RNF31/HOIP and RBCK1/HOIL1, form the linear ubiquitin chain assembly complex (LUBAC) E3 ligase that catalyzes M1-linked polyubiquitination. Mutations in RNF31/HOIP and RBCK/HOIL1 in humans and Sharpin in mice lead to autoinflammation and immunodeficiency, but the mechanism underlying the immune dysregulation remains unclear. We now show that the phenotype of the Sharpincpdm/cpdm mice is dependent on CYLD, a deubiquitinase previously shown to mediate removal of K63-linked polyubiquitin chains. Dermatitis, disrupted splenic architecture, and loss of Peyer's patches in the Sharpincpdm/cpdm mice were fully reversed in Sharpincpdm/cpdm Cyld-/- mice. We observed enhanced association of RIPK1 with the death-signaling Complex II following TNF stimulation in Sharpincpdm/cpdm cells, a finding dependent on CYLD since we observed reversal in Sharpincpdm/cpdm Cyld-/- cells. Enhanced RIPK1 recruitment to Complex II in Sharpincpdm/cpdm cells correlated with impaired phosphorylation of CYLD at serine 418, a modification reported to inhibit its enzymatic activity. The dermatitis in the Sharpincpdm/cpdm mice was also ameliorated by the conditional deletion of Cyld using LysM-cre or Cx3cr1-cre indicating that CYLD-dependent death of myeloid cells is inflammatory. Our studies reveal that under physiological conditions, TNF- and RIPK1-dependent cell death is suppressed by the linear ubiquitin-dependent inhibition of CYLD. The Sharpincpdm/cpdm phenotype illustrates the pathological consequences when CYLD inhibition fails.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number50
DOIs
StatePublished - Dec 14 2021

Keywords

  • TNF
  • apoptosis
  • inflammation
  • ripoptocide
  • ubiquitin

ASJC Scopus subject areas

  • General

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