@article{fe2bc0c0233d400dae6f2291a261cf6f,
title = "Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death",
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.",
keywords = "TNF, apoptosis, inflammation, ripoptocide, ubiquitin",
author = "Ang, {Rosalind L.} and Mark Chan and Diana Legarda and Sundberg, {John P.} and Sun, {Shao Cong} and Gillespie, {Virginia L.} and Nicholas Chun and Heeger, {Peter S.} and Huabao Xiong and Lira, {Sergio A.} and Ting, {Adrian T.}",
note = "Funding Information: We thank the following from the Icahn School of Medicine at Mount Sinai: Mr. Alan Soto from Biorepository and Pathology CoRE services for processing the histology, Ms. Ying Dai from the Comparative Pathology Laboratory in the Center for Comparative Medicine and Surgery for imaging, Drs. Thomas Krauss and Thomas Moran for the use of the Luminex instrument, and Drs. Jesse Gelles and Jerry Chipuk for advice on the use of the IncuCyte instrument. This work was supported by NIH Grant Nos. AI052417 (A.T.T.), AI104521 (A.T.T.), AI132405 (A.T.T. and P.S.H.), DK072201 (S.A.L. and A.T.T.), CA161373 (S.A.L.), AI064639 (S.-C. S), and AR049288 (J.P.S.). This work was also supported by a Senior Research Award Nos. 253097 (A.T.T.) and 330239 (S.A.L.) from the Crohn's and Colitis Foundation of America. R.L.A. was supported by NIH training Grant Nos. AI078892, GM062754, and A1007605. We declare that there are no financial conflicts of interest. Funding Information: ACKNOWLEDGMENTS. We thank the following from the Icahn School of Medicine at Mount Sinai: Mr. Alan Soto from Biorepository and Pathology CoRE services for processing the histology, Ms. Ying Dai from the Comparative Pathology Laboratory in the Center for Comparative Medicine and Surgery for imaging, Drs. Thomas Krauss and Thomas Moran for the use of the Luminex instrument, and Drs. Jesse Gelles and Jerry Chipuk for advice on the use of the IncuCyte instrument. This work was supported by NIH Grant Nos. AI052417 (A.T.T.), AI104521 (A.T.T.), AI132405 (A.T.T. and P.S.H.), DK072201 (S.A.L. and A.T.T.), CA161373 (S.A.L.), AI064639 (S.-C. S), and AR049288 (J.P.S.). This work was also supported by a Senior Research Award Nos. 253097 (A.T.T.) and 330239 (S.A.L.) from the Crohn's and Colitis Foundation of America. R.L.A. was supported by NIH training Grant Nos. AI078892, GM062754, and A1007605. We declare that there are no financial conflicts of interest. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = dec,
day = "14",
doi = "10.1073/pnas.2001602118",
language = "English",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "50",
}