S-Nitrosylation Regulates Nuclear Translocation of Chloride Intracellular Channel Protein CLIC4

Malik, Mariam; Shukla, Anjali; Amin, Palak; Niedelman, Wendy; Lee, Jessica; Jividen, Kasey; Phang, Juanita M.; Ding, Jinhui; Suh, Kwang S.; Curmi, Paul M. G.; Yuspa, Stuart H.

doi:10.1074/jbc.m109.091611

Cited by 37 publications

(41 citation statements)

References 51 publications

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“…For instance, the NO-dependent S-nitrosylation of GAPDH enables its binding to the E3-ubiquitin-ligase Siah, which translocates GAPDH to the nucleus (Hara et al 2005). Malik et al (2010) have recently reported that S-nitrosylation induces the nuclear translocation of the keratinocytes Chloride Intracellular Channel protein (CLIC4), being this mechanism independent of the NO-cGMP pathway. Thus, it will be very interesting to investigate if nuclear translocation of UVR8 may be influenced by UV-B-induced NO production.…”

Section: Discussionmentioning

confidence: 99%

Retracted: Nitric oxide enhances plant ultraviolet‐B protection up‐regulating gene expression of the phenylpropanoid biosynthetic pathway

Tossi¹,

Amenta²,

Lamattina

et al. 2011

Plant Cell & Environment

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The link between ultraviolet (UV)-B, nitric oxide (NO) and phenylpropanoid biosynthetic pathway (PPBP) was studied in maize and Arabidopsis. The transcription factor (TF) ZmP regulates PPBP in maize. A genetic approach using P-rr (ZmP+) and P-ww (ZmP-) maize lines demonstrate that: (1) NO protects P-rr leaves but not P-ww from UV-B-induced reactive oxygen species (ROS) and cell damage; (2) NO increases flavonoid and anthocyanin content and prevents chlorophyll loss in P-rr but not in P-ww and (3)

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Section: Discussionmentioning

confidence: 99%

Retracted: Nitric oxide enhances plant ultraviolet‐B protection up‐regulating gene expression of the phenylpropanoid biosynthetic pathway

Tossi¹,

Amenta²,

Lamattina

et al. 2011

Plant Cell & Environment

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“…However, the modified protein migrated faster than full-length CLIC4, suggesting that it was prone to degradation. This is likely a consequence of the conformational change induced in the protein (13). iNOS knockout macrophages stimulated with LPS and IFNγ also showed reduced CLIC4 nuclear translocation ( Fig.…”

Section: Resultsmentioning

confidence: 98%

“…CLIC4 nuclear translocation is regulated by NOS activity through direct modification of a CLIC4 cysteine residue by NO (13), and nuclear CLIC4 functions to enhance TGF-β signaling (8), the latter being a critical modulator of macrophage deactivation (17). Stimulation with LPS and IFNγ induces Snitrosylation of CLIC4 in macrophages as detected by a biotin switch assay (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The increase is detected in both the cytosolic and nuclear levels of CLIC4 and is concurrent with induction of iNOS protein. CLIC4 nuclear translocation is governed by nitric oxide through S-nitrosylation, which in turn dictates its association with nuclear import proteins (13). iNOS-induced S-nitrosylation and nuclear translocation of CLIC4 in proinflammatory macrophages seems to be essential for down-regulating that part of the proinflammatory program of macrophages that resolves inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…CLIC4 exhibits redox sensitivity in both its soluble and membrane-associated states (11,12). Indeed, a central mechanism for induction of nuclear CLIC4 is nitric oxide (NO)-dependent modification (S-nitrosylation) of the protein that induces a conformational change, enhancing its association with nuclear transporters and thus its nuclear levels (13).…”

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Inducible NOS-induced chloride intracellular channel 4 (CLIC4) nuclear translocation regulates macrophage deactivation

Malik

Jividen

Padmakumar

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear translocation of cytosolic CLIC4 is an essential feature of its proapoptotic and prodifferentiation functions. Here we demonstrate that CLIC4 is induced concurrently with inducible nitric oxide synthase (iNOS) and S-nitrosylated in proinflammatory peritoneal macrophages. Chemical inhibition or genetic ablation of iNOS inhibits S-nitrosylation and nuclear translocation of CLIC4. In macrophages, iNOS-induced nuclear CLIC4 coincides with the proto anti-inflammatory transition of the cells because IL-1β and CXCL1 mRNA remain elevated in CLIC4 and iNOS knockout macrophages at late time points, whereas TNFα mRNA is elevated only in the iNOS knockout macrophages. Active IL-1β remains elevated in CLIC4 knockout macrophages and in macrophages in which CLIC4 nuclear translocation is prevented by the NOS inhibitor L-NAME. Moreover, overexpression of nuclear-targeted CLIC4 down-regulates IL-1β in stimulated macrophages. In mice, genetically null for CLIC4, the number of phagocytosing macrophages stimulated by LPS is reduced. Thus, iNOS-induced nuclear CLIC4 is an essential part of the macrophage deactivation program.protein nitrosylation | IL-1beta | phagocytosis C hloride intracellular channel 4 (CLIC4) is the most wellcharacterized member of a family of channel proteins conserved from Caenorhabditis elegans to humans. Although the chloride-selective channel activity of various members has long been established by multiple groups (1-3), the signaling and adaptor functions of soluble CLIC4 and other members have only recently come to the fore. Soluble CLIC4, originally identified as a p53-and c-myc-responsive proapoptotic protein (4, 5), is important for PKCdependent keratinocyte differentiation (6) and a modulator of TGFβ signaling in multiple cell types (7-9). Many of these proapoptotic and differentiation functions of CLIC4 are dependent on its translocation to the nucleus (6,8,10). CLIC4 exhibits redox sensitivity in both its soluble and membrane-associated states (11,12). Indeed, a central mechanism for induction of nuclear CLIC4 is nitric oxide (NO)-dependent modification (S-nitrosylation) of the protein that induces a conformational change, enhancing its association with nuclear transporters and thus its nuclear levels (13).Recently, a role for CLIC4 has been implicated in innate immunity. CLIC4 is an IRF3-dependent early response gene in LPSstimulated macrophages, transrepressed by the anti-inflammatory activity of the glucocorticoid receptor (14). Moreover, CLIC4 knockout macrophages exhibit dysregulation of multiple inflammatory mediators during the early response to LPS, in part as a consequence of altered IRF3 activity (15). These studies suggest that CLIC4 is important in macrophage early functions in response to stimulation but do not address later aspects of macrophage biology related to deactivation and phagocytosis. Furthermore, information is not available to reveal if the CLIC4 channel or nuclear activity is involved in these functions. Therefore, we investigated the role of CLIC4 activity in infl...

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The distal arthrogryposis‐linked p.R63C variant promotes the stability and nuclear accumulation of TNNT3

Zhang

et al. 2021

Clinical Laboratory Analysis

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Background: Distal arthrogryposis (DA) is comprised of a group of rare developmental disorders in muscle, characterized by multiple congenital contractures of the distal limbs. Fast skeletal muscle troponin-T (TNNT3) protein is abundantly expressed in skeletal muscle and plays an important role in DA. Missense variants in TNNT3 are associated with DA, but few studies have fully clarified its pathogenic role. Methods: Sanger sequencing was performed in three generation of a Chinese family with DA. To determine how the p.R63C variant contributed to DA, we identified a variant in TNNT3 (NM_006757.4): c.187C>T (p.R63C). And then we investigated the effects of the arginine to cysteine substitution on the distribution pattern and the half-life of TNNT3 protein. Results:The protein levels of TNNT3 in affected family members were 0.8-fold higher than that without the disorder. TNNT3 protein could be degraded by the ubiquitin-proteasome complex, and the p.R63C variant did not change TNNT3 nuclear localization, but significantly prolonged its half-life from 2.5 to 7 h, to promote its accumulation in the nucleus. Conclusion:The p.R63C variant increased the stability of TNNT3 and promoted nuclear accumulation, which suggested its role in DA.

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S-Nitrosylation Regulates Nuclear Translocation of Chloride Intracellular Channel Protein CLIC4

Cited by 37 publications

References 51 publications

Retracted: Nitric oxide enhances plant ultraviolet‐B protection up‐regulating gene expression of the phenylpropanoid biosynthetic pathway

Retracted: Nitric oxide enhances plant ultraviolet‐B protection up‐regulating gene expression of the phenylpropanoid biosynthetic pathway

Inducible NOS-induced chloride intracellular channel 4 (CLIC4) nuclear translocation regulates macrophage deactivation

The distal arthrogryposis‐linked p.R63C variant promotes the stability and nuclear accumulation of TNNT3

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