K63-Ubiquitylation and TRAF6 Pathways Regulate Mammalian P-Body Formation and mRNA Decapping

Signals and posttranslational modifications regulating the decapping step in mRNA degradation pathways are poorly defined. In this study we reveal the importance of K63-linked ubiquitylation for the assembly of decapping factors, P-body formation, and constitutive decay of instable mRNAs encoding mediators of inflammation by various experimental approaches. K63-branched ubiquitin chains also regulate IL-1-inducible phosphorylation of the P-body component DCP1a. The E3 ligase TRAF6 binds to DCP1a and indirectly regulates DCP1a phosphorylation, expression of decapping factors, and gene-specific mRNA decay. Mutation of six C-terminal lysines of DCP1a suppresses decapping activity and impairs the interaction with the mRNA decay factors DCP2, EDC4, and XRN1, but not EDC3, thus remodeling P-body architecture. The usage of ubiquitin chains for the proper assembly and function of the decay-competent mammalian decapping complex suggests an additional layer of control to allow a coordinated function of decapping activities and mRNA metabolism in higher eukaryotes. [Display omitted] •K63-linked ubiquitin regulates DCP1a phosphorylation, P-body assembly, and mRNA decay•DCP1a is ubiquitylated and binds to TRAF6 and to ubiquitin binding domains•TRAF6 regulates decapping factors and mRNA decay at multiple levels•DCP1a C-terminal lysines participate in decapping activity and P-body remodeling Tenekeci et al. (2016) describe the relevance of K63-linked ubiquitylation and TRAF6 as regulators of decapping complex assembly and phosphorylation, formation of cytosolic processing (P)-bodies, and the decay of instable inflammatory RNAs.