Selenoprotein K at the intersection of cellular pathways

Selenoprotein K (selenok) is linked to the integrated stress response, which helps cells combat stressors and regain normal function. The selenoprotein contains numerous protein interaction hubs and post-translational modification sites and is involved in protein palmitoylation, vesicle trafficking, and the resolution of ER stress. Anchored to the endoplasmic reticulum (ER) membrane, selenok interacts with protein partners to influence their stability, localization, and trafficking, impacting various cellular functions such as calcium homeostasis, cellular migration, phagocytosis, gene expression, and immune response. Consequently, selenok expression level is linked to cancer and neurodegenerative diseases. Because it contains the reactive amino acid selenocysteine, selenok is likely to function as an enzyme. However, highly unusual for enzymes, the protein segment containing the selenocysteine lacks a stable secondary or tertiary structure, yet it includes multiple interaction sites for protein partners and post-translational modifications. Currently, the reason(s) for the presence of the rare selenocysteine in selenok is not known. Furthermore, of selenok's numerous interaction sites, only some have been sufficiently characterized, leaving many of selenok's potential protein partners to be discovered. In this review, we explore selenok's role in various cellular pathways and its impact on human health, thereby highlighting the links between its diverse cellular functions.