Ji J, Ding K, Luo T, Zhang X, Chen A, Zhang D, Li G, Thorsen F, Huang B, Li X, Wang J

NF-?B signaling plays a critical role in tumor growth and treatment resistance in GBM as in many other cancers. However, the molecular mechanisms underlying high, constitutive NF-?B activity in GBM remains to be elucidated. Here, we screened a panel of tripartite motif (TRIM) family proteins and identified TRIM22 as a ...

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potential activator of NF-?B using an NF-?B driven luciferase reporter construct in GBM cell lines. Knockout of TRIM22 using Cas9-sgRNAs led to reduced GBM cell proliferation, while TRIM22 overexpression enhanced proliferation of cell populations, in vitro and in an orthotopic xenograft model. However, two TRIM22 mutants, one with a critical RING-finger domain deletion and the other with amino acid changes at two active sites of RING E3 ligase (C15/18A), were both unable to promote GBM cell proliferation over controls, thus implicating E3 ligase activity in the growth-promoting properties of TRIM22. Co-immunoprecipitations demonstrated that TRIM22 bound a negative regulator of NF-?B, NF-?B inhibitor alpha (I?B?), and accelerated its degradation by inducing K48-linked ubiquitination. TRIM22 also formed a complex with the NF-?B upstream regulator IKK? and promoted K63-linked ubiquitination, which led to the phosphorylation of both IKK?/? and I?B?. Expression of a non-phosphorylation mutant, srI?B?, inhibited the growth-promoting properties of TRIM22 in GBM cell lines. Finally, TRIM22 was increased in a cohort of primary GBM samples on a tissue microarray, and high expression of TRIM22 correlated with other clinical parameters associated with progressive gliomas, such as wild-type IDH1 status. In summary, our study revealed that TRIM22 activated NF-?B signaling through posttranslational modification of two critical regulators of NF-?B signaling in GBM cells.

Date: Dec. 01, 2020

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