Hypoxia regulates overall mRNA homeostasis by inducing Met1-linked linear ubiquitination of AGO2 in cancer cells

Hypoxia is the most prominent feature in human solid tumors and induces activation of hypoxia-inducible factors and their downstream genes to promote cancer progression. However, whether and how hypoxia regulates overall mRNA homeostasis is unclear. Here we show that hypoxia inhibits global-mRNA decay in cancer cells. Mechanistically, hypoxia induces the interaction of AGO2 with LUBAC, the linear ubiquitin chain assembly complex, which co-localizes with miRNA-induced silencing complex and in turn catalyzes AGO2 occurring Met(1)-linked linear ubiquitination (M1-Ubi). A series of biochemical experiments reveal that M1-Ubi of AGO2 restrains miRNA-mediated gene silencing. Moreover, combination analyses of the AGO2-associated mRNA transcriptome by RIP-Seq and the mRNA transcriptome by RNA-Seq confirm that AGO2 M1-Ubi interferes miRNA-targeted mRNA recruiting to AGO2, and thereby facilitates accumulation of global mRNAs. By this mechanism, short-term hypoxia may protect overall mRNAs and enhances stress tolerance, whereas long-term hypoxia in tumor cells results in seriously changing the entire gene expression profile to drive cell malignant evolution. Met(1)-linked linear ubiquitination (M-1-Ubi) is catalyzed by linear ubiquitin chain assembly complex (LUBAC). Here the authors show that Ago2 protein is M-1-Ubi modified by LUBAC complex under hypoxia condition leading to less association of miRNA target mRNAs to Ago2 protein and de-repression of miRNA targets.

Automated summary

Under hypoxic conditions, the LUBAC complex catalyzes Met(1)-linked linear ubiquitination (M1-Ubi) of Ago2 protein, resulting in reduced association of miRNA target mRNAs with Ago2 protein and de-repression of miRNA targets.