Protein homeostasis (proteostasis) is achieved through a biochemical network that maintains a balanced proteome. Though this network is vast, two main components of it are protein synthesis and degradation. While it is understood that protein synthesis and degradation work in a coordinated fashion to achieve proteostasis, how this coordination occurs is not well understood. Here, we identify 4EBP1, a translation regulator, and PI31, a proteasome regulator, as interactors of the RNA-binding protein, TDP-43. Through detailed biochemical analysis, we show that the 4EBP1-PI31-TDP-43 protein complex forms a translationally inactive mRNA-protein (mRNP) complex. This complex regulates expression levels of TDP-43 itself, and ALS/FTD-causing TDP-43 mutations were found to destabilize the trimeric protein complex, leading to aberrant synthesis of TDP-43 protein. Interestingly, Tankyrase (TNKS)-mediated ADP-ribosylation of PI31 also destabilized the protein complex, thus mimicking the TDP-43 mutants. We then expanded upon this finding by investigating the role of another RNA-binding protein implicated in neurodegeneration, FUS. FUS was found to also form a translationally inactive mRNP complex with 4EBP1 and PI31 to regulate glutamate dehydrogenase 1 (GDH1) protein levels, with addition of TDP-43 enhancing translational suppression. Disease-causing FUSG206S abrogated formation of the 4EBP1-PI31-TDP-43-FUS complex, leading to abnormal synthesis of GDH1 protein, a finding that was corroborated using ALS patient-derived fibroblasts. We found that p38-mediated phosphorylation of PI31 promoted TNKS-mediated ADP-ribosylation of PI31, and that both PTMs mimic pathogenic FUS by destabilizing the protein complex. In vivo studies on mice treated with the TNKS inhibitor, XAV939, revealed a therapeutic effect of this inhibitor on phenotypes associated with neurodegeneration. Overall, our results provide detailed mechanistic insight that underlies the pathogenicity of TDP-43 and FUS disease variants, while also describing novel mechanisms of translational control and the synchronization of protein synthesis and degradation.