SKI complex: A multifaceted cytoplasmic RNA exosome cofactor in mRNA metabolism with links to disease, developmental processes, and antiviral responses

RNA stability and quality control are integral parts of gene expression regulation. A key factor shapingeukaryotic transcriptomes, mainly via 3'-5' exoribonucleolytic trimming or degradation of diversetranscripts in nuclear and cytoplasmic compartments, is the RNA exosome. Precise exosometargeting to various RNA molecules requires strict collaboration with specialized auxiliary factors,which facilitate interactions with its substrates. The predominant class of cytoplasmic RNA targeted bythe exosome are protein-coding transcripts, which are carefully scrutinized for errors duringtranslation. Normal, functional mRNAs are turned over following protein synthesis by the exosome orby Xrn1 5'-3'-exonuclease, acting in concert with Dcp1/2 decapping complex. In turn, aberranttranscripts are eliminated by dedicated surveillance pathways, triggered whenever ribosometranslocation is impaired. Cytoplasmic 3'-5' mRNA decay and surveillance are dependent on the tightcooperation between the exosome and its evolutionary conserved co-factor – the SKI complex (SKIc).Here, we summarize recent findings from structural, biochemical, and functional studies of SKIc rolesin controlling cytoplasmic RNA metabolism, including links to various cellular processes. Mechanism of SKIc action is illuminated by presentation of its spatial structure and details of its interactions withexosome and ribosome. Furthermore, contribution of SKIc and exosome to various mRNA decaypathways, usually converging on recycling of ribosomal subunits, is delineated. A crucial physiologicalrole of SKIc is emphasized by describing association between its dysfunction and devastating humandisease – a trichohepatoenteric syndrome (THES). Eventually, we discuss SKIc functions in theregulation of antiviral defense systems, cell signaling and developmental transitions, emerging frominterdisciplinary investigations.