SPCS3 (signal peptidase complex subunit 3) is a catalytic subunit of the signal peptidase complex (SPC), an essential endoplasmic reticulum membrane enzyme that cleaves signal peptides from secretory pre-proteins with specificity determined by hydrophobic segment length 1. The human SPC exists in two functional paralogs with distinct proteolytic activities, featuring a catalytic triad at an active site that abuts the ER membrane, creating a transmembrane window that locally thins the lipid bilayer 1. SPCS3 plays critical roles in viral infection. It functions as a host restriction factor against chikungunya virus (CHIKV), binding the E1 glycoprotein with antiviral activity; CHIKV undergoes positive selection to overcome this restriction, with E1 residue V220 being essential for counteracting SPCS3-mediated inhibition 23. SPCS3 also participates in normal adipogenesis through retrotransposed paralog genes (Arxes1/2) that evolved tissue-specific functions distinct from the parental gene 4. Clinically, SPCS3 defects contribute to isolated growth hormone deficiency when minor spliceosome mutations impair U12-type intron splicing of the SPCS3 gene, causing pituitary hypoplasia 5. While SPC catalytic subunit SEC11A serves as a prognostic biomarker in head and neck squamous cell carcinoma 6, SPCS3 itself shows expression variation with potential eQTN associations in schizophrenia and bipolar disorder 7.