| Aspect | Key points | Evidence type (review/primary) | Key source (authors, year) | DOI/URL | Publication date (month/year) |
|---|---|---|---|---|---|
| Target identity / disambiguation | Human **SEC63** corresponds to the ER translocon accessory factor described in the literature as part of the **Sec62/Sec63** complex acting on **Sec61**; this matches the UniProt entry **Q9UGP8** (synonyms **DNAJC23/SEC63L** supplied by user context). Literature should be distinguished from yeast Sec63 mechanistic studies, which are informative but not direct human identity evidence (pqac-00000005, pqac-00000023). | Review + mechanistic context | Shao, 2023; Itskanov & Park, 2023 | https://doi.org/10.1091/mbc.e21-09-0451 ; https://doi.org/10.1101/cshperspect.a041250 | 01/2023; 08/2023 |
| Subcellular localization | SEC63 functions at the **endoplasmic reticulum (ER) membrane**, associated with the **Sec61 translocon**; mammalian Sec63 is described as a translocon-associated factor recruited at ER translocation sites (pqac-00000001, pqac-00000005, pqac-00000014). | Review + primary | Sun et al., 2022; Shao, 2023; Gemmer & Förster, 2020 | https://doi.org/10.1083/jcb.202203070 ; https://doi.org/10.1091/mbc.e21-09-0451 ; https://doi.org/10.1242/jcs.231340 | 06/2022; 01/2023; 02/2020 |
| Core molecular function | SEC63 is a **Sec61 accessory factor** that promotes protein import into the ER as part of the **Sec62/Sec63 complex**. Its role is not enzymatic catalysis but **channel regulation/chaperone coupling** during translocation and early folding (pqac-00000008, pqac-00000005, pqac-00000014). | Review | Shao, 2023; Gemmer & Förster, 2020 | https://doi.org/10.1091/mbc.e21-09-0451 ; https://doi.org/10.1242/jcs.231340 | 01/2023; 02/2020 |
| Key interacting partners | Main partners are **Sec61**, **Sec62**, and luminal **BiP/HSPA5**. Sec63 forms a Sec62/Sec63 assembly with Sec61 and recruits BiP through its **J-domain**, coupling channel gating to lumenal chaperone action (pqac-00000000, pqac-00000005, pqac-00000008, pqac-00000012). | Review + primary | Schorr et al., 2019; Shao, 2023 | https://doi.org/10.1101/867762 ; https://doi.org/10.1091/mbc.e21-09-0451 | 12/2019; 01/2023 |
| J-domain / BiP mechanism | SEC63 contains a **J-domain** that recruits and activates **BiP ATPase**; mutation of the conserved **HPD motif** abolishes productive BiP interaction and fails to rescue Sec63-dependent import defects. BiP then helps drive forward translocation and prevent backsliding (pqac-00000000, pqac-00000005, pqac-00000009, pqac-00000010). | Primary + review | Schorr et al., 2019; Sun et al., 2022; Shao, 2023 | https://doi.org/10.1101/867762 ; https://doi.org/10.1083/jcb.202203070 ; https://doi.org/10.1091/mbc.e21-09-0451 | 12/2019; 06/2022; 01/2023 |
| Sec61 gating / lateral gate opening | Structural and mechanistic work supports a model in which **Sec62/Sec63 fully opens or strongly braces open the Sec61 lateral gate**, lowering the energetic barrier for nonoptimal clients to initiate translocation (pqac-00000008, pqac-00000004, pqac-00000012). | Review + mechanistic synthesis | Shao, 2023; Schorr et al., 2019 | https://doi.org/10.1091/mbc.e21-09-0451 ; https://doi.org/10.1101/867762 | 01/2023; 12/2019 |
| Substrate selectivity | SEC63-dependent substrates are enriched for **weak/slowly gating signal peptides**, often with **longer but less hydrophobic H-regions**, **lower C-region polarity**, and sometimes **downstream positive charge clusters** that disrupt efficient translocation without Sec62/Sec63/BiP assistance (pqac-00000006, pqac-00000009). | Primary | Schorr et al., 2019; Sun et al., 2022 | https://doi.org/10.1101/867762 ; https://doi.org/10.1083/jcb.202203070 | 12/2019; 06/2022 |
| Example functional clients / pathway context | In human cells, **ERj3** is a validated Sec63/Sec62/BiP-dependent client; depletion of Sec63 causes **pre-ERj3 accumulation** and impaired mature ERj3 formation, supporting a direct role in selective ER import and folding coordination (pqac-00000000, pqac-00000006). | Primary | Schorr et al., 2019 | https://doi.org/10.1101/867762 | 12/2019 |
| Biological process linkage | SEC63 links **protein translocation** with **protein folding/quality control** by matching weak signal-sequence clients to local BiP availability; stronger signal sequences can bypass Sec63/BiP dependence but may misfold when BiP is limiting (pqac-00000001, pqac-00000009). | Primary | Sun et al., 2022 | https://doi.org/10.1083/jcb.202203070 | 06/2022 |
| Disease association: ADPLD | Germline **SEC63** variants are a recognized cause of **autosomal dominant polycystic liver disease (ADPLD)**; ADPLD genes encode ER proteins and are thought to reduce functional polycystin-1 dosage in liver/kidney cystogenesis (pqac-00000020, pqac-00000025). | Cohort study + disease background | Mizuno et al., 2024; Hu et al., 2023 | https://doi.org/10.34067/KID.0000000000000461 ; https://doi.org/10.1186/s13046-023-02656-7 | 05/2024; 05/2023 |
| Quantitative disease statistics | In a **2024 severe PLD cohort from Japan**, **49** patients were enrolled; **44/49 (90%)** had pathogenic/suspected pathogenic variants. Among genetically solved cases, **SEC63 accounted for 1/44 (2%)**; non-PKD1/PKD2 ADPLD genes collectively accounted for **9/44 (20%)**. Severe PLD was defined as **hTLV >1800 mL/m** (pqac-00000020, pqac-00000021). | Primary cohort study | Mizuno et al., 2024 | https://doi.org/10.34067/KID.0000000000000461 | 05/2024 |
| Cohort phenotype details | In the same cohort, median **hTLV** did not differ significantly between genetically defined ADPKD and ADPLD groups: **4431 mL** (range 1817–9148) vs **3437 mL** (range 1860–8211), **P = 0.77**; height-adjusted kidney volume was larger in ADPKD (**607 vs 179 mL/m, P < 0.01**) (pqac-00000020, pqac-00000021). | Primary cohort study | Mizuno et al., 2024 | https://doi.org/10.34067/KID.0000000000000461 | 05/2024 |
| Non-canonical role in cancer stress adaptation | In hepatocellular carcinoma, SEC63 was reported as a regulator of **metabolic reprogramming under ER stress**, extending beyond canonical translocon function. Upon ER stress, SEC63 supports **ACLY** stabilization, increasing **acetyl-CoA** and lipogenesis to improve ER capacity (pqac-00000017, pqac-00000019, pqac-00000025). | Primary | Hu et al., 2023 | https://doi.org/10.1186/s13046-023-02656-7 | 05/2023 |
| IRE1α phosphorylation / T537 | Hu et al. report that the **IRE1α pathway phosphorylates SEC63 at T537** during ER stress, contributing to SEC63 activation; SEC63 protein abundance changed little, implying regulation mainly by post-translational modification (pqac-00000017, pqac-00000024, pqac-00000025). | Primary | Hu et al., 2023 | https://doi.org/10.1186/s13046-023-02656-7 | 05/2023 |
| ACLY interaction details | SEC63 physically interacts with **ACLY**; the interaction increases with ER stress, depends on the **SEC63 C-terminus**, and maps on ACLY to the **CoA-ligase domain**. ER stress failed to induce ACLY in SEC63-depleted cells (pqac-00000024). | Primary | Hu et al., 2023 | https://doi.org/10.1186/s13046-023-02656-7 | 05/2023 |
| Nuclear / epigenetic role | Under ER stress, SEC63 was reported to **enter the nucleus**, where SEC63 and ACLY raise **nuclear acetyl-CoA**, increase UPR target expression, and promote **Snail1** expression through epigenetic regulation, supporting metastasis (pqac-00000017, pqac-00000025, pqac-00000026). | Primary + model figure | Hu et al., 2023 | https://doi.org/10.1186/s13046-023-02656-7 | 05/2023 |
| Clinical relevance in HCC | SEC63 expression was reported as **upregulated in HCC tissues**, positively correlated with ACLY, and associated with **unfavorable prognosis**; the authors propose the **IRE1α–SEC63–ACLY axis** as a therapeutic concept in HCC (pqac-00000017, pqac-00000025). | Primary | Hu et al., 2023 | https://doi.org/10.1186/s13046-023-02656-7 | 05/2023 |


*Table: This table summarizes the validated identity, ER-translocon function, interacting partners, disease associations, and emerging cancer-related roles of human SEC63. It is useful as a compact evidence map linking canonical translocation biology with recent 2023-2024 disease and stress-response findings.*