The Organellular Chloride Channel Protein CLIC4/mtCLIC Translocates to the Nucleus in Response to Cellular Stress and Accelerates Apoptosis

Suh, Kwang S.; Mutoh, Michihiro; Nagashima, Kunio; Fernández‐Salas, Ester; Edwards, Lindsay E.; Hayes, Denise A.; Crutchley, John; Marin, Keith G; Dumont, Rebecca A.; Levy, Joshua M.; Cheng, Christina; Garfield, Susan H.; Yuspa, Stuart H.

doi:10.1074/jbc.m311632200

Cited by 134 publications

(154 citation statements)

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“…S2). Nitrosylation of CLIC4 is also not a consequence of increased nuclear residence of the protein, because nuclear targeted CLIC4 (14) does not show enhanced levels of modification compared with wild type CLIC4 (data not shown).…”

Section: Nitric Oxide Induces Nuclear Translocation Of Clic4 In Normamentioning

confidence: 93%

“…The * This work was supported, by the National Institutes of Health Intramural soluble, cytosolic portion translocates to the nucleus upon specific stimuli. Nuclear import of CLIC4 involves association of its nuclear localization signal (NLS) with nucleoporins, including importin ␣ and Ran (14). Nuclear targeting of CLIC4 enhances apoptosis in many cell types, whereas inhibiting translocation reduces the apoptotic potential (14).…”

Section: Nuclear Translocation Of Chloride Intracellular Channel Protmentioning

confidence: 99%

“…Nuclear import of CLIC4 involves association of its nuclear localization signal (NLS) with nucleoporins, including importin ␣ and Ran (14). Nuclear targeting of CLIC4 enhances apoptosis in many cell types, whereas inhibiting translocation reduces the apoptotic potential (14). Thus, signaling pathways and post-translational modification(s) modulating CLIC4 nuclear import are extremely attractive targets for cancer therapy.…”

Section: Nuclear Translocation Of Chloride Intracellular Channel Protmentioning

confidence: 99%

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

Malik

Shukla

Amin

et al. 2010

Journal of Biological Chemistry

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Nuclear translocation of chloride intracellular channel protein CLIC4 is essential for its role in Ca2؉ -induced differentiation, stress-induced apoptosis, and modulating TGF-␤ signaling in mouse epidermal keratinocytes. However, post-translational modifications on CLIC4 that govern nuclear translocation and thus these activities remain to be elucidated. The structure of CLIC4 is dependent on the redox environment, in vitro, and translocation may depend on reactive oxygen and nitrogen species in the cell. Here we show that NO directly induces nuclear translocation of CLIC4 that is independent of the NO-cGMP pathway. Indeed, CLIC4 is directly modified by NO through S-nitrosylation of a cysteine residue, as measured by the biotin switch assay. NO enhances association of CLIC4 with the nuclear import proteins importin ␣ and Ran. This is likely a result of the conformational change induced by S-nitrosylated CLIC4 that leads to unfolding of the protein, as exhibited by CD spectra analysis and trypsinolysis of the modified protein. Cysteine mutants of CLIC4 exhibit altered nitrosylation, nuclear residence, and stability, compared with the wild type protein likely as a consequence of altered tertiary structure. Moreover, tumor necrosis factor ␣-induced nuclear translocation of CLIC4 is dependent on nitric-oxide synthase activity. Inhibition of nitric-oxide synthase activity inhibits tumor necrosis factor ␣-induced nitrosylation and association with importin ␣ and Ran and ablates CLIC4 nuclear translocation. These results suggest that S-nitrosylation governs CLIC4 structure, its association with protein partners, and thus its intracellular distribution.CLIC4 (chloride intracellular channel protein 4) belongs to a family of differentially expressed chloride channel proteins that are largely conserved from Caenorhabditis elegans to humans.Various members have been implicated in cell signaling cascades, ranging from stimulation of chloride channel activity by CLIC3 following association with extracellular signal-regulated kinase (ERK) 7 (1) to CLIC5A that is implicated in bone resorption and HCl transport in osteoclasts, in response to phosphorylation by c-Src (2). However, a number of functions of CLIC proteins are independent of channel activity (3, 4).The best characterized of the CLIC family members is CLIC4, identified in our laboratory as a p53 and TNF␣ 2 response gene that is up-regulated during keratinocyte differentiation. CLIC4 has emerged as a crucial player in many physiological processes, including tubular morphogenesis during angiogenesis (5-7), transdifferentiation of mammary fibroblasts to myofibroblasts in response to TGF-␤ (8), and adipocyte differentiation (9). CLIC4 has been established as a significant effector of mouse and human keratinocyte differentiation, associated with G 1 cell cycle arrest and expression of differentiation markers (10).An intriguing aspect of CLIC4 biology is its role as an effector of apoptosis, including p53-and c-Myc-induced apoptosis, as well as in response to cytotoxic and ...

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Section: Nitric Oxide Induces Nuclear Translocation Of Clic4 In Normamentioning

confidence: 93%

Section: Nuclear Translocation Of Chloride Intracellular Channel Protmentioning

confidence: 99%

Section: Nuclear Translocation Of Chloride Intracellular Channel Protmentioning

confidence: 99%

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

Malik

Shukla

Amin

et al. 2010

Journal of Biological Chemistry

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“…constructs have been previously characterized (10). Treatment with both CLIC4 vectors decreased IL-1β and iNOS following stimulation of cells (Fig.…”

Section: Clic4 Knockout Macrophages Show Enhanced Levels Of Il-1β Andmentioning

confidence: 95%

“…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)(8)(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).…”

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confidence: 99%

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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Mitochondrial Channels in Neurodegeneration

Peixoto

Kinnally

Pavlov

2015

The Functions, Disease‐Related Dysfunctions, and Therapeutic Targeting of Neuronal Mitochondria

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The Organellular Chloride Channel Protein CLIC4/mtCLIC Translocates to the Nucleus in Response to Cellular Stress and Accelerates Apoptosis

Cited by 134 publications

References 36 publications

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

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

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

Mitochondrial Channels in Neurodegeneration

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