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

Chu, Yihang; Soberon, Valeria; Glockner, L.; Beyaert, Rudi; Massoumi, Ramin; Loo, Geert; Krappmann, Daniel; Schmidt-Supprian, Marc

doi:10.4049/jimmunol.1200396

Cited by 20 publications

(16 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This suggests that these ubiquitin editing enzymes are differentially regulated and have separate roles during normal aging. Along such lines, A20 and CYLD have been shown to have separate roles during B-cell activation with Toll-like receptor ligands (Chu et al, 2012). While in this study we implicate elevated A20 as a cause of ADMD, obtaining a more comprehensive understanding of how these deubiquitinases are regulated, their overlapping/distinct roles, and clarity in our understanding of their role during aging is important to understand how the innate immune system is altered during aging.…”

Section: Discussionmentioning

confidence: 99%

Elevated A20 contributes to age-dependent macrophage dysfunction in the lungs

Hinojosa

Babu

Rahman

et al. 2014

Experimental Gerontology

View full text Add to dashboard Cite

Advanced age is associated with chronic low-grade inflammation (i.e. inflamm-aging) and poor macrophage function that includes a weak pro-inflammatory cytokine response to bacteria and diminished phagocytosis (i.e. age-dependent macrophage dysfunction [ADMD]). One reason for this is that ADMD is associated with poor NFκB and MAPK activation following Toll-like receptor stimulation (Boyd et al., 2012)(Boyd et al., 2012)(Boyd et al., 2012)[1][1][1](Boyd et al., 2012). Herein, we tested the hypothesis that inflamm-aging induces production of A20, a cytosolic and homeostatic suppressor of the NFκB and MAPK signaling cascades that deubiquitinates (i.e. inactivates) the common upstream signaling molecule TRAF6, and this is responsible for ADMD. Western blots and immunohistochemistry comparing tissues from young, mature, and aged C57BL/6 mice indicated that A20 was strongly elevated in the lungs of aged mice but not in other tissues. Elevated A20 was also detected in alveolar macrophages (AM) from aged mice. In contrast CYLD, a second deubiquitinase that also negatively regulates the NFκB pathway was decreased with aging. Following co-incubation of AM with the bacteria Streptococcus pneumoniae, TRAF6 polyubiquitination was diminished in AM isolated from aged versus young mice. A20 production was inducible in the J774A.1 macrophage cell line and C57BL/6 AM by overnight incubation with TNFα but not IL-6. Retrovirus-induced expression of A20 in J774A.1 cells resulted in their diminished production of IL-6 following exposure to S. pneumoniae but had no effect on levels of phagocytosis. Overnight incubation of AM from young mice with TNFα also resulted in a dampened IL-6 response to S. pneumoniae. Finally, dietary supplementation of aged mice with anti-inflammatory n-3 polyunsaturated fatty acids in the form of fish oil lowered lung A20 levels and enhanced resistance, including a 100-fold reduction in bacterial titers in the lungs, to experimental challenge with S. pneumoniae. We conclude that elevated A20 due to TNFα partially explains the ADMD phenotype and that ADMD is potentially reversible.

show abstract

Section: Discussionmentioning

confidence: 99%

Elevated A20 contributes to age-dependent macrophage dysfunction in the lungs

Hinojosa

Babu

Rahman

et al. 2014

Experimental Gerontology

View full text Add to dashboard Cite

show abstract

“…Array data based on RNA transcript abundance at Genecards.org indicates that CYLD is found in low levels in a large percentage of somatic cells, with immune cells expressing more of it [24]. Unlike other deubiquitinases such as A20, CYLD is constitutively expressed, albeit at a low basal level [25, 26]. Regulation of both CYLD transcription and translation is highly variable, with multiple mechanisms available, including direct phosphorylation by kinases, treatment with allosteric caspase inhibitors like zVAD, protealytic cleavage, external serum receptor transduction and subsequent modification via kinases [such as SRF to MAPK and CaMKII pathways], control by other transcription factors and gene interactions, and direct binding by miRNAs [27–37].…”

Section: Cyld Overviewmentioning

confidence: 99%

CYLD-Mediated Signaling and Diseases

Mathis¹,

Lai²,

Qu³

et al. 2015

CDT

View full text Add to dashboard Cite

The conserved cylindromatosis (CYLD) codes for a deubiquitinating enzyme and is a crucial regulator of diverse cellular processes such as immune responses, inflammation, death, and proliferation. It directly regulates multiple key signaling cascades, such as the Nuclear Factor kappa B [NF-kB] and the Mitogen-Activated Protein Kinase (MAPK) pathways, by its catalytic activity on polyubiquitinated key intermediates. Several lines of emerging evidence have linked CYLD to the pathogenesis of various maladies, including cancer, poor infection control, lung fibrosis, neural development, and now cardiovascular dysfunction. While CYLD-mediated signaling is cell type and stimuli specific, the activity of CYLD is tightly controlled by phosphorylation and other regulators such as Snail. This review explores a broad selection of current and past literature regarding CYLD’s expression, function and regulation with emerging reports on its role in cardiovascular disease.

show abstract

“…The other known substrates of MALT1 are all negative regulators of canonical NF-kB signaling. MALT1-dependent cleavage of the two ubiquitin editing enzymes, A20 and cylindromatosis (CYLD), downregulates their activity (12)(13)(14)(15). MALT1 also cleaves RelB, priming it for proteasomedependent degradation (16) and resulting in modulation of canonical NF-kB activation via the release of RelA and c-Rel.…”

mentioning

confidence: 99%

Deficiency of MALT1 Paracaspase Activity Results in Unbalanced Regulatory and Effector T and B Cell Responses Leading to Multiorgan Inflammation

Bornancin

Renner

Touil

et al. 2015

The Journal of Immunology

119

214

View full text Add to dashboard Cite

The paracaspase MALT1 plays an important role in immune receptor-driven signaling pathways leading to NF-κB activation. MALT1 promotes signaling by acting as a scaffold, recruiting downstream signaling proteins, as well as by proteolytic cleavage of multiple substrates. However, the relative contributions of these two different activities to T and B cell function are not well understood. To investigate how MALT1 proteolytic activity contributes to overall immune cell regulation, we generated MALT1 protease-deficient mice (Malt1PD/PD) and compared their phenotype with that of MALT1 knockout animals (Malt1−/−). Malt1PD/PD mice displayed defects in multiple cell types including marginal zone B cells, B1 B cells, IL-10–producing B cells, regulatory T cells, and mature T and B cells. In general, immune defects were more pronounced in Malt1−/− animals. Both mouse lines showed abrogated B cell responses upon immunization with T-dependent and T-independent Ags. In vitro, inactivation of MALT1 protease activity caused reduced stimulation-induced T cell proliferation, impaired IL-2 and TNF-α production, as well as defective Th17 differentiation. Consequently, Malt1PD/PD mice were protected in a Th17-dependent experimental autoimmune encephalomyelitis model. Surprisingly, Malt1PD/PD animals developed a multiorgan inflammatory pathology, characterized by Th1 and Th2/0 responses and enhanced IgG1 and IgE levels, which was delayed by wild-type regulatory T cell reconstitution. We therefore propose that the pathology characterizing Malt1PD/PD animals arises from an immune imbalance featuring pathogenic Th1- and Th2/0-skewed effector responses and reduced immunosuppressive compartments. These data uncover a previously unappreciated key function of MALT1 protease activity in immune homeostasis and underline its relevance in human health and disease.

show abstract

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

Cited by 20 publications

References 51 publications

Elevated A20 contributes to age-dependent macrophage dysfunction in the lungs

Elevated A20 contributes to age-dependent macrophage dysfunction in the lungs

CYLD-Mediated Signaling and Diseases

Deficiency of MALT1 Paracaspase Activity Results in Unbalanced Regulatory and Effector T and B Cell Responses Leading to Multiorgan Inflammation

Contact Info

Product

Resources

About