SPC12 (SPCS1) is the 12-kDa subunit of the mammalian SPC; it spans the membrane twice with N and C termini facing the cytosol and minimal lumenal domains, indicating a non-catalytic role.

SPCS1 interacts with HCV NS2 and E2 and is required for assembly of infectious HCV particles, without affecting structural-protein processing, host secretion, entry, RNA replication, or release.

SPCS1 is required for proper cleavage of flavivirus structural proteins (prM, E) and secretion of viral particles; loss reduces yield of WNV, DENV, ZIKV, YFV, JEV, and HCV.

SPCS1 interacts with the transmembrane domains of flaviviral NS2B and is required for post-translational processing of JEV proteins and virion assembly, but not entry, RNA replication, or translation.

Cryo-EM structures of the two human SPC paralogs (SEC11A and SEC11C variants); the active site abuts the ER membrane where a transmembrane window collectively formed by all subunits locally thins the bilayer, generating specificity based on signal-peptide hydrophobic-segment length.

Loss of SPCS1 specifically impairs SPC-mediated processing of the HCV E2-p7 junction (a suboptimal cleavage site); efficient separation of E2 and p7 renders SPCS1 dispensable for assembly, establishing that SPCS1 facilitates assembly by enhancing presentation of the suboptimal E2-p7 junction to the SPC active site, paralleling its role at the flaviviral C-prM junction.

A pooled CRISPR/Cas9 screen in placental trophoblasts identified ER membrane complex and signal peptide processing genes as Zika virus host factors, and validated SPCS1 as crucial for ZIKV replication in trophoblasts.

Non-catalytic accessory subunit of the ER signal peptidase complex (SPC-A with SEC11A and SPC-C with SEC11C, each also containing SPCS2 and SPCS3); multi-pass ER membrane protein; dispensable for SPC enzymatic activity; host factor for flavivirus/HCV structural-protein processing and assembly.