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DDX39B interacts with the pattern recognition receptor pathway to inhibit NF-?B and sensitize to alkylating chemotherapy.

ABSTRACT: BACKGROUND:Nuclear factor-?B (NF-?B) plays a prominent role in promoting inflammation and resistance to DNA damaging therapy. We searched for proteins that modulate the NF-?B response as a prerequisite to identifying novel factors that affect sensitivity to DNA damaging chemotherapy. RESULTS:Using streptavidin-agarose pull-down, we identified the DExD/H-box RNA helicase, DDX39B, as a factor that differentially interacts with ?B DNA probes. Subsequently, using both RNA interference and CRISPR/Cas9 technology, we demonstrated that DDX39B inhibits NF-?B activity by a general mechanism involving inhibition of p65 phosphorylation. Mechanistically, DDX39B mediates this effect by interacting with the pattern recognition receptor (PRR), LGP2, a pathway that required the cellular response to cytoplasmic double-stranded RNA (dsRNA). From a functional standpoint, loss of DDX39B promoted resistance to alkylating chemotherapy in glioblastoma cells. Further examination of DDX39B demonstrated that its protein abundance was regulated by site-specific sumoylation that promoted its poly-ubiquitination and degradation. These post-translational modifications required the presence of the SUMO E3 ligase, PIASx-?. Finally, genome-wide analysis demonstrated that despite the link to the PRR system, DDX39B did not generally inhibit interferon-stimulated gene expression, but rather acted to attenuate expression of factors associated with the extracellular matrix, cellular migration, and angiogenesis. CONCLUSIONS:These results identify DDX39B, a factor with known functions in mRNA splicing and nuclear export, as an RNA-binding protein that blocks a subset of the inflammatory response. While these findings identify a pathway by which DDX39B promotes sensitization to DNA damaging therapy, the data also reveal a mechanism by which this helicase may act to mitigate autoimmune disease.

SUBMITTER: Szymura SJ

PROVIDER: S-EPMC7093963 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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DDX39B interacts with the pattern recognition receptor pathway to inhibit NF-κB and sensitize to alkylating chemotherapy.

Szymura Szymon J SJ Bernal Giovanna M GM Wu Longtao L Zhang Zhongqin Z Crawley Clayton D CD Voce David J DJ Campbell Paige-Ashley PA Ranoa Diana E DE Weichselbaum Ralph R RR Yamini Bakhtiar B

BMC biology 20200324 1

<h4>Background</h4>Nuclear factor-κB (NF-κB) plays a prominent role in promoting inflammation and resistance to DNA damaging therapy. We searched for proteins that modulate the NF-κB response as a prerequisite to identifying novel factors that affect sensitivity to DNA damaging chemotherapy.<h4>Results</h4>Using streptavidin-agarose pull-down, we identified the DExD/H-box RNA helicase, DDX39B, as a factor that differentially interacts with κB DNA probes. Subsequently, using both RNA interference ...[more]

PMID: 32209106

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DDX39B interacts with the pattern recognition receptor pathway to inhibit NF-?B and sensitize to alkylating chemotherapy.

Publications

DDX39B interacts with the pattern recognition receptor pathway to inhibit NF-κB and sensitize to alkylating chemotherapy.

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