SHARPIN is a key regulator of immune and inflammatory responses

Zhe Wang, Christopher S. Potter, John P. Sundberg, Harm Hogenesch

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Mice with spontaneous mutations in the Sharpin gene develop chronic proliferative dermatitis that is characterized by eosinophilic inflammation of the skin and other organs with increased expression of type 2 cytokines and dysregulated development of lymphoid tissues. The mutant mice share phenotypic features with human hypereosinophilic syndromes. The biological function of SHARPIN and how its absence leads to such a complex inflammatory phenotype in mice are poorly understood. However, recent studies identified SHARPIN as a novel modulator of immune and inflammatory responses. The emerging mechanistic model suggests that SHARPIN functions as an important adaptor component of the linear ubiquitin chain assembly complex that modulates activation of NF-κB signalling pathway, thereby regulating cell survival and apoptosis, cytokine production and development of lymphoid tissues. In this review, we will summarize the current understanding of the ubiquitin-dependent regulatory mechanisms involved in NF-κB signalling, and incorporate the recently obtained molecular insights of SHARPIN into this pathway. Recent studies identified SHARPIN as an inhibitor of β1-integrin activation and signalling, and this may be another mechanism by which SHARPIN regulates inflammation. Furthermore, the disrupted lymphoid organogenesis in SHARPIN-deficient mice suggests that SHARPIN-mediated NF-κB regulation is important for de novo development of lymphoid tissues.

Original languageEnglish (US)
Pages (from-to)2271-2279
Number of pages9
JournalJournal of Cellular and Molecular Medicine
Volume16
Issue number10
DOIs
StatePublished - Oct 1 2012
Externally publishedYes

Keywords

  • Chronic dermatitis
  • Eosinophilic dermatitis
  • Immune system
  • Inflammation
  • Lymphoid organogenesis
  • NF-κB
  • Scaly skin disease
  • Sharpin
  • Ubiquitination

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

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