The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation

Ahmed, Noman; Zeng, Minghui; Sinha, Indrajit; Polin, Lisa; Wei, Wei Zen; Rathinam, Chozhavendan; Flavell, Richard A.; Massoumi, Ramin; Venuprasad, K.

doi:10.1038/ni.2157

Cited by 144 publications

(153 citation statements)

References 49 publications

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“…Itch 2/2 and Ndfip1 2/2 mice were described previously (11,14). C57BL/6 mice were purchased from Charles River Laboratory.…”

Section: Micementioning

confidence: 99%

“…Flag-Itch, Flag-Tak1, hemagglutinin (HA)-Ub (wild-type [WT]), HX-Itch (C830A), and Myc-Ndfip1 were described previously (14,15). HA-Ube2L3 (UbcH7) was obtained from Addgene (cat.…”

Section: Plasmid Construction and Cell Transfectionmentioning

confidence: 99%

“…Lentivirus transfection was performed as described earlier (14). Expression clones were created by Gateway cloning technology, according to the manufacturer's instructions (Invitrogen).…”

Section: Lentiviral Transductionmentioning

confidence: 99%

“…Immunoprecipitation was performed using anti-Flag Ab. Tak1-associated Ub was analyzed by immunoblot using Ab against HA, as we described previously (14).…”

Section: Ubiquitination Assaymentioning

confidence: 99%

“…All clone sequences were confirmed. Transient transfection of 293T cells was performed using Lipofectamine 2000 (Invitrogen), according to the manufacturer's instructions (14).…”

Section: Plasmid Construction and Cell Transfectionmentioning

confidence: 99%

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Ndfip1 Regulates Itch Ligase Activity and Airway Inflammation via UbcH7

Kathania

Zeng

Yadav

et al. 2015

The Journal of Immunology

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The ubiquitin-ligating enzyme (E3) Itch plays a crucial role in the regulation of inflammation, and Itch deficiency leads to severe airway inflammation. However, the molecular mechanisms by which Itch function is regulated remain elusive. In this study, we found that nontypeable Haemophilus influenzae induces the association of Itch with Ndfip1. Both Itch−/− and Ndfip1−/− mice exhibited severe airway inflammation in response to nontypeable Haemophilus influenza, which was associated with elevated expression of proinflammatory cytokines. Ndfip1 enhanced Itch ligase activity and facilitated Itch-mediated Tak1 ubiquitination. Mechanistically, Ndfip1 facilitated recruitment of ubiquitin-conjugating enzyme (E2) UbcH7 to Itch. The N-terminal region of Ndfip1 binds to UbcH7, whereas the PY motif binds to Itch. Hence, Ndfip1 acts as an adaptor for UbcH7 and Itch. Reconstitution of full-length Ndfip1 but not the mutants that fail to interact with either UbcH7 or Itch, restored the defect in Tak1 ubiquitination and inhibited elevated proinflammatory cytokine expression by Ndfip1−/− cells. These results provide new mechanistic insights into how Itch function is regulated during inflammatory signaling, which could be exploited therapeutically in inflammatory diseases.

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“…Itch 2/2 and Ndfip1 2/2 mice were described previously (11,14). C57BL/6 mice were purchased from Charles River Laboratory.…”

Section: Micementioning

confidence: 99%

“…Flag-Itch, Flag-Tak1, hemagglutinin (HA)-Ub (wild-type [WT]), HX-Itch (C830A), and Myc-Ndfip1 were described previously (14,15). HA-Ube2L3 (UbcH7) was obtained from Addgene (cat.…”

Section: Plasmid Construction and Cell Transfectionmentioning

confidence: 99%

“…Lentivirus transfection was performed as described earlier (14). Expression clones were created by Gateway cloning technology, according to the manufacturer's instructions (Invitrogen).…”

Section: Lentiviral Transductionmentioning

confidence: 99%

“…Immunoprecipitation was performed using anti-Flag Ab. Tak1-associated Ub was analyzed by immunoblot using Ab against HA, as we described previously (14).…”

Section: Ubiquitination Assaymentioning

confidence: 99%

“…All clone sequences were confirmed. Transient transfection of 293T cells was performed using Lipofectamine 2000 (Invitrogen), according to the manufacturer's instructions (14).…”

Section: Plasmid Construction and Cell Transfectionmentioning

confidence: 99%

See 3 more Smart Citations

Ndfip1 Regulates Itch Ligase Activity and Airway Inflammation via UbcH7

Kathania

Zeng

Yadav

et al. 2015

The Journal of Immunology

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The RING domain of RING Finger 11 (RNF11) protein binds Ubc13 and inhibits formation of polyubiquitin chains

et al. 2018

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The Really Interesting New Gene (RING) Finger protein 11 (RNF11) is a subunit of the A20 ubiquitin-editing complex that ensures the transient nature of inflammatory responses. Although the role of RNF11 as a negative regulator of NF-κB signalling is well-documented, the molecular mechanisms that underpin this function are poorly understood. Here, we show that RNF11 binds both Ubc13 and the Ubc13~ubiquitin conjugate tightly and with similar affinity, but has minimal E3 ligase activity. Remarkably, RNF11 appears to bind Ubc13 so tightly that it outcompetes the E1 and an active E3 ligase. As a consequence, RNF11 may regulate the activity of E3s that rely on Ubc13 for ubiquitin chain assembly by limiting the availability of Ubc13 and its conjugate.

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GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma

Jin

et al. 2021

Clinical & Translational Med

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Background Aberrant TAK1 (transforming growth factor β‐activated kinase 1) activity is known to be involved in a variety of malignancies, but the regulatory mechanisms of TAK1 remain poorly understood. GRAMD4 (glucosyltransferase Rab‐like GTPase activator and myotubularin domain containing 4) is a newly discovered p53‐independent proapoptotic protein with an unclear role in HCC (hepatocellular carcinoma). Results In this research, we found that GRAMD4 expression was lower in HCC samples, and its downregulation predicted worse prognosis for patients after surgical resection. Functionally, GRAMD4 inhibited HCC migration, invasion and metastasis. Mechanistically, GRAMD4 interacted with TAK1 to promote its protein degradation, thus, resulting in the inactivation of MAPK (Mitogen‐activated protein kinase) and NF‐κB pathways. Furthermore, GRAMD4 was proved to recruit ITCH (itchy E3 ubiquitin protein ligase) to promote the ubiquitination of TAK1. Moreover, high expression of TAK1 was correlated with low expression of GRAMD4 in HCC patients. Conclusions GRAMD4 inhibits the migration and metastasis of HCC, mainly by recruiting ITCH to promote the degradation of TAK1, which leads to the inactivation of MAPK and NF‐κB signalling pathways.

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The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation

Cited by 144 publications

References 49 publications

Ndfip1 Regulates Itch Ligase Activity and Airway Inflammation via UbcH7

Ndfip1 Regulates Itch Ligase Activity and Airway Inflammation via UbcH7

The RING domain of RING Finger 11 (RNF11) protein binds Ubc13 and inhibits formation of polyubiquitin chains

GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma

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