| SELS (selenoprotein S, SELENOS) is an endoplasmic reticulum and perinuclear membrane protein of the selenoprotein family that participates in ER‐associated degradation and unfolded protein response pathways and is synthesized as two major transcript variants with distinct 3′UTRs that differentially support selenocysteine incorporation. The polypeptide contains a luminal N‑terminal segment, a single transmembrane helix, and a cytosolic C‑terminus that harbors the penultimate selenocysteine residue, and structural studies indicate that Sec and a neighboring cysteine can form a selenosulfide redox pair compatible with reductase activity toward disulfide‑linked substrates in the ERAD machinery. SELS engages ubiquitinated misfolded proteins, ER membrane complexes, and the AAA‑ATPase p97/VCP, and functions as one of the membrane adaptors that couple recognition of misfolded ER proteins to their retro‑translocation into the cytosol and subsequent degradation by the ubiquitin–proteasome system, linking its redox activity and membrane position to ER protein quality control. The SELS gene produces at least two mRNA isoforms through alternative 3′UTR splicing: variant 2 retains a functional SECIS element that permits recoding of the UGA codon as selenocysteine and yields full‑length selenoprotein S, whereas variant 1 lacks the SECIS element and produces a truncated protein without Sec, and both transcripts are broadly expressed with variant 2 usually more abundant. Cis‑elements in the variant 2 3′UTR, including a proximal conserved stem‑loop and a region immediately downstream of the SECIS, modulate the efficiency of Sec insertion, so SELS protein output and the proportion of Sec‑containing versus truncated species are controlled post‑transcriptionally by 3′UTR structure. SELS expression is induced by ER stress signals and inflammatory cytokines, and work on selenoproteins in human disease indicates that SELS contributes to removal of misfolded proteins from the ER and participates in cellular stress and inflammatory responses alongside other ER selenoproteins such as Sep15. |
