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

Tsagaratou, Ageliki; Kontoyiannis, Dimitris L.; Mosialos, George

doi:10.1371/journal.pone.0016397

Cited by 5 publications

(3 citation statements)

References 23 publications

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“…We have demonstrated that loss of Cyld function does not affect NF-κB activity but enhances JNK activity in renal tubular epithelial cells contributing the tubulointerstitial inflammation of IgA nephropathy [33]. Notably, truncation of deubiquitinating domain of CYLD specifically in myelomonocytic cells suppresses the development of lethal LPS-induced endotoxic shock and the accumulation of thioglycollate-elicited peritoneal macrophages with hyperactivation of NF-κB [45]. Because the over-expression of exogenous CYLD may cover the endogenous function of CYLD in VSMCs [23], aforementioned, we believe that results obtained by Cyld loss-of-function RNAi approach reflects more precisely the intrinsic function of CYLD in VSMCs.…”

Section: Discussionmentioning

confidence: 99%

A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells

Liu

Han

et al. 2012

Biochemical and Biophysical Research Communications

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CYLD, a deubiquitinating enzyme (DUB), is a critical regulator of diverse cellular processes, ranging from proliferation and differentiation to inflammatory responses, via regulating multiple key signaling cascades such as nuclear factor kappa B (NF-κB) pathway. CYLD has been shown to inhibit vascular lesion formation presumably through suppressing NF-κB activity in vascular cells. However, herein we report a novel role of CYLD in mediating pro-inflammatory responses in vascular smooth muscle cells (VSMCs) via a mechanism independent of NF-κB activity. Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNFα)-induced mRNA expression of pro-inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic VSMCs (RASMCs). The CYLD deficiency led to increases in the basal NF-κB transcriptional activity in RASMCs; however, did not affect the TNFα-induced NF-κB activity. Intriguingly, the TNFα-induced IκB phosphorylation was enhanced in the CYLD deficient RASMCs. While knocking down of Cyld decreased slightly the basal expression levels of IκBα and IκBβ proteins, it did not alter the kinetics of TNFα-induced IκB protein degradation in RASMCs. These results indicate that CYLD suppresses the basal NF-κB activity and TNFα-induced IκB kinase activation without affecting TNFα-induced NF-κB activity in VSMCs. In addition, knocking down of Cyld suppressed TNFα-induced activation of mitogen activated protein kinases (MAPKs) including extracellular signal-activated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 in RASMCs. TNFα-induced RASMC migration and monocyte adhesion to RASMCs were inhibited by the Cyld knockdown. Finally, immunochemical staining revealed a dramatic augment of CYLD expression in the injured coronary artery with neointimal hyperplasia. Taken together, our results uncover an unexpected role of CYLD in promoting inflammatory responses in VSMCs via a mechanism involving MAPK activation but independent of NF-κB activity, contributing to the pathogenesis of vascular disease.

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Section: Discussionmentioning

confidence: 99%

A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells

Liu

Han

et al. 2012

Biochemical and Biophysical Research Communications

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“…A20 deficiency in B cells induces the expansion of myeloid and T cells, resulting in splenomegaly and chronic inflammation (11). It seems possible that loss of CYLD function in myelomonocytic cells, which impairs their responses to inflammatory stimuli (36), counteracts the inflammation caused by A20-deficient B cells to some extent. This could explain the reduction of splenocyte numbers in CD19Cre/A20 F/F CYLD 2/2 mice compared with CD19Cre/A20 F/F mice.…”

Section: Loss Of Cyld Does Not Exacerbate the Defects In A20-deficienmentioning

confidence: 99%

A20 and CYLD Do Not Share Significant Overlapping Functions during B Cell Development and Activation

Chu

Soberon

Glockner

et al. 2012

The Journal of Immunology

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The ubiquitin-editing enzyme A20 (TNFAIP3) and the deubiquitinase CYLD are central negative regulators of NF-kappa B signaling. Both can act by removing nonproteolytic K63-linked polyubiquitin chains from an overlapping set of signaling molecules. In B cells, A20 deficiency results in hyperactivity, loss of immune homeostasis, inflammation, and autoimmunity. The reported consequences of CYLD deficiency are controversial, ranging from an absence of effects to dramatic B cell hyperplasia. These differences could be due to varying compensation for the loss of CYLD function by A20. Therefore, to explore potential overlapping physiological functions between A20 and CYLD, we generated and characterized A20/CYLD double-deficient B cells. Interestingly, the lack of both A20 and CYLD did not exacerbate the developmental defects and hyperresponsive activity of A20-deficient B cells. In addition, the extent of B cell activation after in vitro stimulation with anti-CD40, LPS, and CpG was comparable in B cells lacking A20/CYLD and A20 alone. However, in response to BCR cross-linking, we observed small but reproducible additive effects of the lack of A20 and CYLD. Taken together, our results demonstrate that A20 and CYLD do not share significant functions during B cell development and activation. The Journal of Immunology, 2012, 189: 4437-4443

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“…Furthermore, a conditional gene targeting approach was used to create CyldΔ9 mice, which has enhanced cell resistance to LPS-induced endotoxic shock, while the CYLD-deficient macrophages failed to accumulate to the inflammatory site. These results suggest potential benefits of targeting CYLD with inhibitors in control of certain forms of pathogenic inflammation [19]. …”

Section: The Host Immune Responses Regulated By Dubsmentioning

confidence: 99%

Deubiquitinating Enzymes as Promising Drug Targets for Infectious Diseases

Nanduri

Suvarnapunya²,

Venkatesan³

et al. 2013

CPD

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Deubiquitinating enzymes (DUBs) remove ubiquitin and ubiquitin-like modifications from proteins and they have been known to contribute to processes relevant in microbial infection, such as immune responses pathways. Numerous viral and bacterial DUBs have been identified, and activities of several host DUBs are known to be modulated during the infection process, either by a pathogen or by a host. Recently there have been attempts to take advantage of this feature and design therapeutic inhibitors of DUBs that can be used to limit the spread of infection. This review is focused on exploring the potential of DUBs in the treatment of infectious diseases.

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

Cited by 5 publications

References 23 publications

A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells

A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells

A20 and CYLD Do Not Share Significant Overlapping Functions during B Cell Development and Activation

Deubiquitinating Enzymes as Promising Drug Targets for Infectious Diseases

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