ISG15 modification of Ubc13 suppresses its ubiquitin-conjugating activity

Takeuchi, Tomoharu; Yokosawa, Hideyoshi

doi:10.1016/j.bbrc.2005.08.034

Cited by 74 publications

(55 citation statements)

References 25 publications

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“…Likewise, it would be important to elucidate the biological consequences of Serpin 2A, Stat1, Jak1, PLC␥1, and Erk1/2 ISGylation (8,26). Most recently, ISG15 modification via the ε-amino group of a lysine residue has been confirmed via mass spectrometry analysis of ISGylated Ubc13 (45), and a large number of additional potential ISG15 target proteins have been identified from immunoaffinity purification and mass spectrometry analysis (6,38,44,45). The study of these new target proteins may reveal a role of protein ISGylation in additional biological pathways.…”

Section: Discussionmentioning

confidence: 98%

Ube1L and Protein ISGylation Are Not Essential for Alpha/Beta Interferon Signaling

Kim¹,

Yan²,

Malakhova³

et al. 2006

Molecular and Cellular Biology

118

108

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The expression of ubiquitin-like modifier ISG15 and its conjugation to target proteins are highly induced by interferon (IFN) stimulation and during viral and bacterial infections. However, the biological significance of this modification has not been clearly understood. To investigate the function of protein modification by ISG15, we generated a mouse model deficient in UBE1L, an ISG15-activating enzyme. Ube1L ؊/؊ mice did not produce ISG15 conjugates but expressed free ISG15 normally. ISGylation has been implicated in the reproduction and innate immunity. However, Ube1L؊/؊ mice were fertile and exhibited normal antiviral responses against vesicular stomatitis virus and lymphocytic choriomeningitis virus infection. Our results indicate that UBE1L and protein ISGylation are not critical for IFN-␣/␤ signaling via JAK/STAT activation. Moreover, using Ube1L/Ubp43 double-deficient mice, we showed that lack of UBP43, but not the increase of protein ISGylation, is related to the increased IFN signaling in Ubp43-deficient mice.

show abstract

Section: Discussionmentioning

confidence: 98%

Ube1L and Protein ISGylation Are Not Essential for Alpha/Beta Interferon Signaling

Kim¹,

Yan²,

Malakhova³

et al. 2006

Molecular and Cellular Biology

118

108

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“…ISG15 could potentially interfere with the ubiquitin pathway at the level of E1, E2, and E3. Indeed, ISGylation of Ubc13 (ubiquitin E2) is shown to disrupt its ability to form the thioester bond with ubiquitin (33,34). Whether other ubiquitin E2 functions are similarly inhibited by ISG15 through E2 ISGylation is not known.…”

Section: Discussionmentioning

confidence: 99%

Elevated Expression of ISG15 in Tumor Cells Interferes with the Ubiquitin/26S Proteasome Pathway

Desai¹,

Haas

Wood³

et al. 2006

Cancer Research

169

221

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IFN-stimulatory gene factor 15 (ISG15) is a ubiquitin-like protein, which is conjugated to many cellular proteins. However, its role in protein degradation is unclear. Here, we show that ISG15 is highly elevated and extensively conjugated to cellular proteins in many tumors and tumor cell lines. The increased levels of ISG15 in tumor cells were found to be associated with decreased levels of polyubiquitinated proteins. Specific knockdown of ISG15 expression using ISG15-specific small interfering RNA (siRNA) was shown to increase the levels of polyubiquitinated proteins, suggesting an antagonistic role of ISG15 in regulating ubiquitin-mediated protein turnover. Moreover, siRNA-mediated down-regulation of the major E2 for ISG15 (UbcH8), which blocked the formation of ISG15 protein conjugates, also increased the levels of polyubiquitinated proteins. Together, our results suggest that the ISG15 pathway, which is deregulated during tumorigenesis, negatively regulates the ubiquitin/proteasome pathway by interfering with protein polyubiquitination/ degradation. (Cancer Res 2006; 66(2): 921-8)

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“…However, unlike the ubiquitination system, where ubiquitin tagged proteins is degraded in a proteasome dependent manner, ISGylation system promotes stabilization of ISG15 conjugated proteins by interfering with the ubiquitin/26S proteasome pathway (Zhao et al, 2005;Pitha-Rowe et al, 2007). For example, ISGylation of the ubiquitin E2 conjugating enzyme UBC13 disrupts its ability to form thioester bond with ubiquitin, which in turn promotes sustained activation of associated proteins (Takeuchi et al, 2005;Zou et al, 2005). It has also been shown that conjugation of ISG15 with proteins other than those involved in the ubiquitin pathway promotes sustained activation of the ISGylated protein.…”

Section: Introductionmentioning

confidence: 99%

Interferon Stimulated Gene - ISG15 is a Potential Diagnostic Biomarker in Oral Squamous Cell Carcinomas

Laljee¹,

Muddaiah²,

Salagundi³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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ISG15 modification of Ubc13 suppresses its ubiquitin-conjugating activity

Cited by 74 publications

References 25 publications

Ube1L and Protein ISGylation Are Not Essential for Alpha/Beta Interferon Signaling

Ube1L and Protein ISGylation Are Not Essential for Alpha/Beta Interferon Signaling

Elevated Expression of ISG15 in Tumor Cells Interferes with the Ubiquitin/26S Proteasome Pathway

Interferon Stimulated Gene - ISG15 is a Potential Diagnostic Biomarker in Oral Squamous Cell Carcinomas

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