Late-stage Disulfides are Indispensable for a Healthy Gut Lining

While most catalysts of disulfide bond formation reside in the endoplasmic reticulum, Quiescin Sulfhydryl Oxidase 1 (QSOX1) is uniquely found in the Golgi apparatus of most cell types and in the extracellular environment. QSOX1 was shown to be essential for proper assembly of extracellular matrix in cultured cells, but little is known about the contribution of its activity to the formation of extracellular biomaterials in a physiological context. To bridge this gap we generated knockout mice lacking the enzyme and tested the effect of QSOX1 deficiency on organ development and function.

Secretory organs such as the lungs and the gastrointestinal tract normally express high levels of QSOX1. Though no gross abnormal development was apparent in QSOX1 knockout mice, their colons showed lowered levels and impaired extracellular organization of MUC2, the major mucin secreted to the colon and a highly disulfide-bonded glycoprotein. In accordance with defective mucus generation, QSOX1 knockout mice were more susceptible to induced colitis, developing disease symptoms earlier and more severely than wild-type mice. Histochemical analysis confirmed increased inflammation and degradation of colons in the knockouts. Additionally, the microbiome, which resides in and feeds on colon mucus, was significantly different between QSOX1 knockout mice and their co-housed wild-type littermates. It therefore appears that QSOX1, a disulfide catalyst that works downstream of the canonical protein oxidation site in the secretory pathway, takes part in construction of the protective mucus of the colon.