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

Abstract

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.

Proteasome‐independent functions of lysine‐63 polyubiquitination in plants

“…These include, for example, P-body formation and mRNA processing in response to inflammation (Tenekeci et al, 2016), membrane recruitment of AKT kinase (Yang et al, 2009) and regulation of complex formation in NFjB signaling by K63 polyubiquitinated proteins and free unanchored K63-linked Ub chains (Xia et al, 2009), and will not be discussed in this review. (Yin et al, 2007), two physiological processes found to be governed by auxin transport.…”

TNF receptor associated factor 6 interacts with ALS-linked misfolded superoxide dismutase 1 and promotes aggregation

“…TRAF6 is a multifaceted protein; it is a central player at the interface of inflammatory signaling and the autophagy machinery (27)(28)(29)(30) and plays a role in mitophagy (34,35) and RNA metabolism (85,86), all of which are recurrent pathomechanistic themes in ALS, independent of genetic etiology. As such, we speculate that TRAF6 dysfunction due to mutant/misfolded SOD1 binding could affect cellular integrity at various levels, and in different cellular compartments.…”

The IκB kinase complex is a regulator of mRNA stability

“…As we have shown here, IKK‐mediated phosphorylation of EDC4 regulates its association with DCP1a and DCP2 in response to DNA damage, promoting the formation of P‐bodies. Similarly, phosphorylation of DCP1a by JNK or ERK was shown to alter its localization to P‐bodies (Rzeczkowski et al , ; Aizer et al , ; Tenekeci et al , ). Post‐translational modifications might not only affect interaction among constitutive components of these cellular bodies, but also change recruitment of RBPs and therefore of their target mRNAs.…”