CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN

Legarda, Diana; Justus, Scott J.; Ang, Rosalind L.; Rikhi, Nimisha; Li, Wenjing; Moran, Thomas M.; Zhang, Jianke; Mizoguchi, Emiko; Zelic, Matija; Kelliher, Michelle A.; Blander, J. Magarian; Ting, Adrian T.

doi:10.1016/j.celrep.2016.05.032

Cited by 91 publications

(100 citation statements)

References 69 publications

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“…Caspase-8 targets the deubiquitinase CYLD preventing RIPK1 initiation of necroptosis (Legarda et al, 2016). S. aureus has been shown previously to activate caspases-8, -3 and -7 in keratinocytes (Soong et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling

et al. 2016

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Staphylococcus aureus trigger inflammation through inflammasome activation and recruitment of neutrophils, responses critical for pathogen clearance but associated with substantial tissue damage. We postulated that necroptosis, cell death mediated by the RIPK1/RIPK3/MLKL pathway, would function to limit pathological inflammation. In models of skin infection or sepsis, Mlkl−/− mice had high bacterial loads, inability to limit IL.1b production and excessive inflammation. Similarly, mice treated with RIPK1 or RIPK3 inhibitors had increased bacterial loads in a model of sepsis. Ripk3−/− mice exhibited increased staphylococcal clearance and decreased inflammation in skin and systemic infection, due to direct effects of RIPK3 on IL-1b activation and apoptosis. In contrast to Casp1/4 −/− mice with defective S. aureus killing, the poor outcomes of Mlkl−/− mice could not be attributed to impaired phagocytic function. We conclude that necroptotic cell death limits the pathological inflammation induced by S. aureus.

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Section: Resultsmentioning

confidence: 99%

Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling

et al. 2016

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“…Subsequent studies have found an absolute requirement for IFNα/β priming in the death of MΦs by necroptosis (163, 170). Thus, the combinatorial impact of TNFα and type I IFNs has the potential to drive MΦs necroptosis in autoimmune diseases, such as severe AA.…”

Section: Mechanisms Of Ifnα/β-mediated Hspc Impairmentmentioning

confidence: 99%

Hematopoietic Stem Cell Regulation by Type I and II Interferons in the Pathogenesis of Acquired Aplastic Anemia

2016

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Aplastic anemia (AA) occurs when the bone marrow fails to support production of all three lineages of blood cells, which are necessary for tissue oxygenation, infection control, and hemostasis. The etiology of acquired AA is elusive in the vast majority of cases but involves exhaustion of hematopoietic stem cells (HSC), which are usually present in the bone marrow in a dormant state, and are responsible for lifelong production of all cells within the hematopoietic system. This destruction is immune mediated and the role of interferons remains incompletely characterized. Interferon gamma (IFNγ) has been associated with AA and type I IFNs (alpha and beta) are well documented to cause bone marrow aplasia during viral infection. In models of infection and inflammation, IFNγ activates HSCs to differentiate and impairs their ability to self-renew, ultimately leading to HSC exhaustion. Recent evidence demonstrating that IFNγ also impacts the HSC microenvironment or niche, raises new questions regarding how IFNγ impairs HSC function in AA. Immune activation can also elicit type I interferons, which may exert effects both distinct from and overlapping with IFNγ on HSCs. IFNα/β increase HSC proliferation in models of sterile inflammation induced by polyinosinic:polycytidylic acid and lead to BM aplasia during viral infection. Moreover, patients being treated with IFNα exhibit cytopenias, in part due to BM suppression. Herein, we review the current understanding of how interferons contribute to the pathogenesis of acquired AA, and we explore additional potential mechanisms by which interferons directly and indirectly impair HSCs. A comprehensive understanding of how interferons impact hematopoiesis is necessary in order to identify novel therapeutic approaches for treating AA patients.

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“…Interestingly, whereas caspase-8-mediated cleavage occurs outside the catalytic domain of CYLD, the released C-terminal fragment containing its USP domain is unstable and is degraded by the proteasome. This CYLD proteolysis is important to inhibit necroptosis in macrophages stimulated with LPS (Legarda et al, 2016). A20 is another DUB that is inactivated by proteolytic cleavage (Coornaert et al, 2008).…”

Section: Regulation Of Dub Function By Proteolytic Processingmentioning

confidence: 99%

Mechanisms of regulation and diversification of deubiquitylating enzyme function

Leznicki

Kulathu

2017

Journal of Cell Science

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Deubiquitylating (or deubiquitinating) enzymes (DUBs) are proteases that reverse protein ubiquitylation and therefore modulate the outcome of this post-translational modification. DUBs regulate a variety of intracellular processes, including protein turnover, signalling pathways and the DNA damage response. They have also been linked to a number of human diseases, such as cancer, and inflammatory and neurodegenerative disorders. Although we are beginning to better appreciate the role of DUBs in basic cell biology and their importance for human health, there are still many unknowns. Central among these is the conundrum of how the small number of ∼100 DUBs encoded in the human genome is capable of regulating the thousands of ubiquitin modification sites detected in human cells. This Commentary addresses the biological mechanisms employed to modulate and expand the functions of DUBs, and sets directions for future research aimed at elucidating the details of these fascinating processes.This article is part of a Minifocus on Ubiquitin Regulation and Function. For further reading, please see related articles: 'Exploitation of the host cell ubiquitin machinery by microbial effector proteins' by Yi-Han Lin and Matthias P. Machner (J. Cell Sci. 130, 1985-1996. 'Cell scientist to watch -Mads Gyrd-Hansen' (J. Cell Sci. 130, 1981-1983.

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CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN

Cited by 91 publications

References 69 publications

Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling

Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling

Hematopoietic Stem Cell Regulation by Type I and II Interferons in the Pathogenesis of Acquired Aplastic Anemia

Mechanisms of regulation and diversification of deubiquitylating enzyme function

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