Truncation of the Deubiquitinating Domain of CYLD in Myelomonocytic Cells Attenuates Inflammatory Responses

Ageliki Tsagaratou,George Mosialos,Dimitris L Kontoyiannis,Maria G Masucci

doi:10.1371/journal.pone.0016397

Abstract

The cylindromatosis tumor suppressor (CYLD) is a deubiquitinating enzyme that has been implicated in various aspects of adaptive and innate immune responses. Nevertheless, the role of CYLD in the function of specific types of immune cells remains elusive. In this report we have used conditional gene targeting in mice to address the role of the deubiquitinating activity of CYLD in the myelomonocytic lineage. Truncation of the deubiquitinating domain of CYLD specifically in myelomonocytic cells impaired the development of lethal LPS-induced endotoxic shock and the accumulation of thioglycollate-elicited peritoneal macrophages. Our data establish CYLD as a regulator of monocyte-macrophage activation in response to inflammatory stimuli and identify it as a potential target for therapeutic intervention in relevant inflammatory disorders in humans.

Highlights

Cyld was identified as the predisposition gene for the tumor syndrome of familial cylindromatosis
It mediates the suppression of the NF-kB, JNK, p38 and Wnt pathways in a manner that depends on its deubiquitinating activity
The use of mouse models of cylindromatosis tumor suppressor (CYLD) deficiency has implicated the protein in the regulation of multiple physiological processes including T cell development and activation, B cell homeostasis and function, osteoclastogenesis and spermatogenesis (Reviewed in [2])

Summary

Introduction

Cyld was identified as the predisposition gene for the tumor syndrome of familial cylindromatosis. CYLD downregulation sensitizes mice to various pathological conditions that include chemically induced skin tumor formation as well as colitis-associated cancer [3,4]. In all these cases a broad range of CYLD-targeted proteins could be recognized, establishing CYLD as a multi-tasking deubiquitinating enzyme implicated in the fine tuning of many developmental and physiological processes. Another study showed that Cyld-deficient mice were more resistant to lethal pulmonary infection caused by Streptococcal pneumoniae This was attributed to enhanced p38 activation and subsequent elevated expression of PAI-1 [5,6]. In all the aforementioned studies mice bearing obligatory null alleles were used making it impossible to discern the cell-specific contribution of CYLD to the observed phenotype [8]

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Results