Could the cell nucleus be a new destination for QSOX1 under thermal stress?

Quiescin/sulfhydryl oxidase 1 (QSOX1) is a thiol oxidase that exists in two isoforms, QSOX1a, which contains a transmembrane (TM) domain, a short extraluminal domain, and a luminal catalytic domain, and QSOX1b, which lacks the TM domain and remains soluble. QSOX1 is localized in the ER, Golgi, secretory vesicles, endosomes, and the extracellular environment. In this study, we demonstrate via immunofluorescence that QSOX1 translocates to the nucleus in response to heat (43 °C) and cold (4 °C) stress, occurring as early as 15 min post-exposure in L929 fibroblasts. Orthogonal views of confocal microscopy images reveal that QSOX1 is predominantly nucleoplasmic. This nuclear translocation was further confirmed through cell fractionation followed by immunoblotting, which also identified QSOX1a as the primary isoform present in nuclear fractions. RT-qPCR analysis revealed an increase in QSOX1a mRNA levels, with a significant upregulation observed specifically after cold stress. Finally, QSOX1 knockdown sensitized fibroblasts to cold stress-induced cell death, indicating a potential cytoprotective role for QSOX1a under these conditions. Our findings suggest that the cell nucleus may serve as a novel subcellular destination for QSOX1a during cold stress. Based on existing literature, we proposed a hypothesis to explain the nuclear translocation, possibly via a lateral diffusion-retention mechanism. The biological significance and molecular mechanisms underlying this translocation, however, warrant further investigation.