The SKI mRNA surveillance pathway

In a manner similar to the proteasome’s role in protein degradation, the SKI complex consisting of helicase SKIC2 (formerly known as SKIV2L, OMIM600478) and its cofactors SKIC3 and SKIC48 (formerly knows as TTC37 and WDR61) form a macromolecular assembly which associates with the cytoplasmic exosome to degrade RNA molecules. SKIC2, possesses two additional co-factors namely FOCAD and AVEN. Whereas AVEN acts cooperatively with the SKI complex in translation surveillance by preventing ribosome stalling, FOCAD’s exact role is not understood. Our study uncovered that FOCAD is essential for maintaining the proteostatic levels of SKIC2 and SKIC3 in various human cell lines and in an animal model of the disease. The significant clinical overlap between the FOCAD-deficiency and Tricho-Hepato-Enteric Syndromes (THES) caused by mutations in SKIC2 or SKIC3, lends credence to the notion that FOCAD is directly involved in the SKI mRNA surveillance pathway.