HSCARG inhibits activation of NF-κB by interacting with IκB kinase-β

Gan, Qini; Li, Tingting; Lian, Min; Zheng, Xiaofeng

doi:10.1242/jcs.054007

Cited by 20 publications

(29 citation statements)

References 49 publications

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“…co-IP and western blot analyses were performed following procedures described previously (33). Briefly, HEK293T cells were transfected with the indicated plasmids.…”

Section: Methodsmentioning

confidence: 99%

HSCARG, a novel regulator of H2A ubiquitination by downregulating PRC1 ubiquitin E3 ligase activity, is essential for cell proliferation

Zhang

Zheng

2014

Nucleic Acids Research

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Histone H2A ubiquitination plays critical roles in transcriptional repression and deoxyribonucleic acid (DNA) damage response. More attention has been focused on ubiquitin E3 ligases of H2A, however, less is known about the negative regulators of H2A ubiquitination. Here we identified HSCARG as a new negative regulatory protein for H2A ubiquitination and found a possible link between regulator of H2A ubiquitination and cell cycle. Mechanistically, HSCARG interacts with polycomb repressive complex 1 (PRC1) and deubiquitinase USP7 and inhibits PRC1 ubiquitination in a USP7-dependent manner. As ubiquitination of PRC1 is critical for its E3 ligase activity toward H2A, HSCARG and USP7 are further shown to decrease the level of H2A ubiquitination. Moreover, we demonstrated that HSCARG is involved in DNA damage response through affecting the level of H2A ubiquitination and localization of RAP80 at lesion points. Knockout of HSCARG results in persistent activation of checkpoint signaling and leads to cell cycle arrest. This study unravels a novel mechanism for the regulation of H2A ubiquitination and elucidates how regulators of H2A ubiquitination affect cell cycle.

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“…co-IP and western blot analyses were performed following procedures described previously (33). Briefly, HEK293T cells were transfected with the indicated plasmids.…”

Section: Methodsmentioning

confidence: 99%

HSCARG, a novel regulator of H2A ubiquitination by downregulating PRC1 ubiquitin E3 ligase activity, is essential for cell proliferation

Zhang

Zheng

2014

Nucleic Acids Research

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“…In our previous study, we demonstrated that HSCARG interacts with IKK β and suppresses its phosphorylation by promoting the interaction between PP2A and IKK β , 32 which provided one of the possible mechanisms to explain how HSCARG inhibits IKK β phosphorylation and NF- κ B activity. To further investigate which protein was the direct interaction partner of HSCARG, we carried out in vitro pull-down assays between HSCARG and NEMO or IKK β .…”

Section: Discussionmentioning

confidence: 95%

“…HSCARG is a newly identified NF- κ B inhibitor. 32 Here we elucidated the detailed mechanism in which HSCARG inhibits NF- κ B activity. HSCARG interacts with USP7 and inhibits the polyubiquitination of NEMO, which decreases proteasomal degradation of I κ B α and further inhibits NF- κ B activity (Figure 6).…”

Section: Discussionmentioning

confidence: 98%

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HSCARG downregulates NF-κB signaling by interacting with USP7 and inhibiting NEMO ubiquitination

Guan

et al. 2014

Cell Death Dis

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Nuclear factor κB (NF-κB) signaling is a central pathway that participates in a variety of key processes, including immunity, inflammation, cell growth and differentiation. The activity of NF-κB is strictly regulated by a cluster of proteins, and modifications of these proteins either promote or suppress signal transduction at various steps. Here we demonstrated that HSCARG suppresses TNFα-stimulated NF-κB signaling under physiological conditions. We elucidated the detailed mechanism through which HSCARG inhibits NF-κB activation. HSCARG interacts with NEMO and suppresses polyubiquitination of NEMO by interacting with the deubiquitinase USP7. HSACRG attenuates its inhibitory effect on NEMO ubiquitination in USP7 knockdown cells, and inhibition of NEMO polyubiquitination by USP7 is impaired in HSCARG−/− cells as well. Moreover, we demonstrated that USP7 is a negative regulator of TNFα-stimulated NF-κB activity. Altogether, our data indicate that HSCARG and USP7 function in concert in inhibiting polyubiquination of NEMO, thus inhibiting NF-κB activity.

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“…HSCARG (also named NmrA-like family domain-containing protein 1 or NMRAL1) is a newly-identified NADPH sensor and negative regulator of NF-κB [29]. It contains a Rossmann-fold in the N terminus and forms an asymmetrical dimer with only one subunit occupied by one NADP molecule [30].…”

Section: Introductionmentioning

confidence: 99%

HSCARG Negatively Regulates the Cellular Antiviral RIG-I Like Receptor Signaling Pathway by Inhibiting TRAF3 Ubiquitination via Recruiting OTUB1

Peng

Zheng

2014

PLoS Pathog

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RIG-I like receptors (RLRs) recognize cytosolic viral RNA and initiate innate immunity; they increase the production of type I interferon (IFN) and the transcription of a series of antiviral genes to protect the host organism. Accurate regulation of the RLR pathway is important for avoiding tissue injury induced by excessive immune response. HSCARG is a newly reported negative regulator of NF-κB. Here we demonstrated that HSCARG participates in innate immunity. HSCARG inhibited the cellular antiviral response in an NF-κB independent manner, whereas deficiency of HSCARG had an opposite effect. After viral infection, HSCARG interacted with tumor necrosis receptor-associated factor 3 (TRAF3) and inhibited its ubiquitination by promoting the recruitment of OTUB1 to TRAF3. Knockout of HSCARG attenuated the de-ubiquitination of TRAF3 by OTUB1, and knockdown of OTUB1 abolished the effect of HSCARG. HSCARG also interacted with Ikappa-B kinase epsilon (IKKε) after viral infection and impaired the association between TRAF3 and IKKε, which further decreased the phosphorylation of IKKε and interferon response factor 3 (IRF3), thus suppressed the dimerization and nuclear translocation of IRF3. Moreover, knockdown of TRAF3 dampened the inhibitory effect of IFN-β transcription by HSCARG, suggesting that TRAF3 is necessary for HSCARG to down-regulate RLR pathway. This study demonstrated that HSCARG is a negative regulator that enables balanced antiviral innate immunity.

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HSCARG inhibits activation of NF-κB by interacting with IκB kinase-β

Cited by 20 publications

References 49 publications

HSCARG, a novel regulator of H2A ubiquitination by downregulating PRC1 ubiquitin E3 ligase activity, is essential for cell proliferation

HSCARG, a novel regulator of H2A ubiquitination by downregulating PRC1 ubiquitin E3 ligase activity, is essential for cell proliferation

HSCARG downregulates NF-κB signaling by interacting with USP7 and inhibiting NEMO ubiquitination

HSCARG Negatively Regulates the Cellular Antiviral RIG-I Like Receptor Signaling Pathway by Inhibiting TRAF3 Ubiquitination via Recruiting OTUB1

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