Post-translational ER transport is mediated by a membrane protein complex consisting of the Sec61 complex and the Sec62-Sec63 subcomplex; establishes mammalian SEC63 association with the Sec61 translocon.

Yeast two-hybrid identification of nucleoredoxin (NRX) as a SEC63 interaction partner, linking SEC63 to Wnt signaling and proposing a mechanism for SEC63-related polycystic liver disease.

Depletion of Sec61alpha, Sec62 and Sec63 has different effects on cotranslational and post-translational ER transport; establishes SEC63 as an ER-membrane translocation component.

Sec63 and the lumenal chaperone BiP act as auxiliary translocation components during chaperone-mediated Sec61 channel gating for import of small presecretory proteins; the SEC63 J-domain (H132) is required for efficient translocation.

Marginally hydrophobic signal sequences and transmembrane domains cause transient retention at the Sec61 translocon and require luminal BiP for efficient translocation. Sec63 is co-translationally recruited to the translocation site and mediates BiP binding to incoming polypeptides, which releases translocationally paused nascent chains and ensures proper folding in the ER; increasing signal-sequence hydrophobicity bypasses Sec63/BiP dependence.

In hepatocellular carcinoma, ER stress activates SEC63 via IRE1alpha-mediated phosphorylation at T537; SEC63 stabilizes ACLY (ATP-citrate lyase) to increase acetyl-CoA and lipid biosynthesis, and also enters the nucleus to coordinate with ACLY in epigenetically upregulating Snail1, promoting metastasis. SEC63 is upregulated in HCC, correlates with ACLY, and predicts unfavorable prognosis.

In a Japanese cohort of 49 patients with severe polycystic liver disease (height-adjusted total liver volume >1800 mL/m), 44/49 (90%) carried pathogenic or suspected pathogenic variants in polycystic disease genes; SEC63 accounted for 1/44 (2%) of genetically solved cases, supporting its inclusion in diagnostic ADPLD gene panels.

In intact human cells, 22 novel Sec62/Sec63-dependent substrates were identified in addition to ERj3; SEC62/SEC63 clients share signal peptides with longer but less hydrophobic H-regions and lower C-region polarity, and a slowly gating signal peptide combined with a downstream positively charged cluster is decisive for the Sec62/Sec63 requirement. The Sec62/Sec63 complex may support Sec61 opening by direct interaction with the cytosolic N-terminus of Sec61alpha or via recruitment of BiP to ER-lumenal loop 7 of Sec61alpha; these insights inform the etiology of SEC63-linked polycystic liver disease.

Review/article hybrid combining siRNA depletion of ER targeting and insertion components (including SEC62/SEC63) with label-free quantitative proteomics to define client types and rules of engagement, framing SEC63 as a substrate-selective Sec61 translocon accessory/co-chaperone.

SEC63 mediates cotranslational and post-translational transport of precursors across the ER, cooperates with SEC62 and HSPA5/BiP to import small presecretory proteins into the Sec61 channel; multi-pass ER membrane protein with a luminal DnaJ J-domain (104-165); required for PKD1 biogenesis; LoF variants cause PCLD2.