| Entity / aspect | Summary for human GET4 / TRC35 | Key evidence / mechanism | Evidence type | Key references |
|---|---|---|---|---|
| Identity | **GET4** encodes the human **guided entry of tail-anchored proteins factor 4**; common aliases include **TRC35**, **C7orf20**, **CEE**, and **CGI-20**. It is the metazoan homolog of yeast **Get4** and matches the UniProt target **Q7L5D6** discussed in the GET/TRC literature (pqac-00000007, pqac-00000015). | Conserved assignment of metazoan Get4 to TRC35/GET4 in reviews and comparative pathway analyses (pqac-00000007, pqac-00000015). | Comparative pathway mapping, review | Qin 2023, *The Innovation Life*, doi: https://doi.org/10.59717/j.xinn-life.2023.100013 ; Pool 2022, *IJMS*, doi: https://doi.org/10.3390/ijms23073773 |
| Primary molecular function | GET4/TRC35 is a **cytosolic pretargeting scaffold/adaptor** in the **GET/TRC pathway** for **tail-anchored (TA) membrane proteins**. It does **not catalyze a chemical reaction**; instead, it helps organize factors that capture, shield, and hand off hydrophobic TA transmembrane domains to the targeting ATPase **TRC40/ASNA1** for ER delivery (pqac-00000000, pqac-00000003, pqac-00000007, pqac-00000012). | Reviews and structural work place Get4/TRC35 in the upstream relay between SGTA/Sgt2 and Get3/TRC40, promoting efficient substrate loading onto the ATPase (pqac-00000000, pqac-00000003, pqac-00000012). | Review, biochemical, cryo-EM | Shan 2019, *JBC*, doi: https://doi.org/10.1074/jbc.rev119.006197 ; Keszei 2021, *Nat Struct Mol Biol*, doi: https://doi.org/10.1038/s41594-021-00690-7 |
| Core complex composition | In mammals, GET4/TRC35 is a stable component of the **BAG6–UBL4A–GET4** pretargeting complex (often treated as the metazoan counterpart of yeast Get4/Get5). **BAG6** binds both **GET4/TRC35** and **UBL4A/Get5**; **SGTA** acts upstream in TA capture; **TRC40/ASNA1** is the downstream targeting ATPase; ER insertion is completed at **WRB/CAML** (pqac-00000002, pqac-00000007, pqac-00000009, pqac-00000013). | Human/metazoan studies and reviews describe a heterotrimeric BAG6–UBL4A–TRC35 complex that receives TA substrates from SGTA and transfers them to TRC40 for delivery to WRB/CAML (pqac-00000009, pqac-00000013). | Structural, biochemical, review | Mock 2017, *PNAS*, doi: https://doi.org/10.1073/pnas.1702940114 ; Farkas & Bohnsack 2021, *J Cell Biol*, doi: https://doi.org/10.1083/jcb.202105004 |
| Mechanistic role in TA targeting: capture and handoff | Canonical handoff sequence: **ribosome / chaperones → SGTA → BAG6–UBL4A–GET4(TRC35) → TRC40/ASNA1 → WRB/CAML at the ER**. GET4/TRC35 helps create the recruitment platform that positions upstream factors for **TA substrate transfer** to Get3/TRC40; in metazoan cryo-EM, UBL4A-cBAG6-GET4 forms a recruitment platform above the Get3 substrate chamber (pqac-00000012, pqac-00000017). | Keszei et al. defined a metazoan pretargeting architecture where Get4 helps position Ubl4a/BAG6 to recruit SGTA and promote substrate transfer; mutations affecting the secondary Get3–Get4 interface impaired **SGTA→Get3 transfer** without blocking Get3 substrate capture per se (pqac-00000012). | Cryo-EM, crosslinking, biochemical | Keszei 2021, *Nat Struct Mol Biol*, doi: https://doi.org/10.1038/s41594-021-00690-7 ; Figure context (pqac-00000017) |
| Ribosome association / early targeting stage | GET4/TRC35 functions **early**, close to the site of synthesis. Reviews describe the mammalian pretargeting machinery as **ribosome-associated** or **ribosome-proximal**, with TA capture occurring at or near the ribosome before handoff to TRC40; Get4/TRC35 was also identified among ribosome-associated proteins in comparative analyses (pqac-00000000, pqac-00000010, pqac-00000015). | Pool 2022 describes TRC35 within ribosome-associated BAG6 complexes; Qin 2023 discusses ribosome-proximal capture and competition near the tunnel exit; comparative analysis notes Get4 identification in ribosome-associated screens (pqac-00000000, pqac-00000010, pqac-00000015). | Review, proteomic / comparative inference | Pool 2022, *IJMS*, doi: https://doi.org/10.3390/ijms23073773 ; Qin 2023, *The Innovation Life*, doi: https://doi.org/10.59717/j.xinn-life.2023.100013 |
| Subcellular localization | Best-supported localization is **cytosolic**, within the **pretargeting complex** acting before ER membrane insertion. Functionally, GET4/TRC35 is linked to ER targeting through its interaction network, but it is not itself the ER insertase; ER insertion is mediated by **WRB/CAML** after TRC40 delivery (pqac-00000007, pqac-00000009, pqac-00000013). | Cytosolic pretargeting role is consistently reported in reviews and structural studies; downstream localization step is ER membrane insertion by WRB/CAML, not by GET4 itself (pqac-00000007, pqac-00000009, pqac-00000013). | Review, structural | Mock 2017, *PNAS*, doi: https://doi.org/10.1073/pnas.1702940114 ; Farkas & Bohnsack 2021, *J Cell Biol*, doi: https://doi.org/10.1083/jcb.202105004 |
| Control of BAG6 nucleo-cytoplasmic distribution | A key human-specific mechanistic finding is that **TRC35 masks the BAG6 nuclear localization sequence (NLS)**, thereby **retaining BAG6 in the cytosol**. Overexpression of TRC35 increases cytosolic retention of BAG6; structural analysis showed TRC35 occludes the first basic cluster of the BAG6 NLS (pqac-00000009, pqac-00000016). | Human crystal structure and biochemical assays support direct Bag6–TRC35 interfaces; buried surface metrics and mutational effects showed that physiological complex assembly regulates BAG6 localization (pqac-00000009, pqac-00000016). | Crystal structure, biochemical, cell biology | Mock 2017, *PNAS*, doi: https://doi.org/10.1073/pnas.1702940114 |
| Quality control role: substrate triage | GET4/TRC35 participates in a module that links **TA targeting** with **cytosolic quality control**. BAG6-containing complexes can direct hydrophobic or mislocalized clients either toward productive loading onto TRC40 or toward **ubiquitin-proteasome degradation**, helping prevent aggregation of exposed transmembrane segments (pqac-00000000, pqac-00000002, pqac-00000013, pqac-00000014). | Reviews emphasize the dual targeting-versus-degradation role of BAG6 complexes; Hagiwara 2023 further links this machinery to aggregate/proteotoxic stress responses (pqac-00000013, pqac-00000014). | Review, biochemical | Farkas & Bohnsack 2021, *J Cell Biol*, doi: https://doi.org/10.1083/jcb.202105004 ; Hagiwara 2023, *Biochem J*, doi: https://doi.org/10.1042/bcj20230267 |
| Quality control role: RNF126 and TRC35 stability | Human studies indicate that **unassembled or mutant TRC35** can become a target of **RNF126-mediated ubiquitylation** in the BAG6-associated quality-control network. Proper Bag6 association protects TRC35; Bag6-disrupting mutants increased Ub-conjugated TRC35 and lowered steady-state TRC35 levels, reversible by proteasome inhibition (**MG132**) (pqac-00000016). | Mock et al. identified RNF126 as a Bag6-associated E3 ligase implicated in TRC35 ubiquitylation and showed that disrupted physiological Bag6–TRC35 interaction destabilizes TRC35 (pqac-00000016). | Structural, biochemical, ubiquitination assay | Mock 2017, *PNAS*, doi: https://doi.org/10.1073/pnas.1702940114 |
| Proteotoxic stress effects (2023) | In 2023, proteotoxic stress studies showed that the TA recognition complex is stress-sensitive: **polyQ aggregates**, **proteasome inhibition**, and **CCCP-induced mitochondrial depolarization** promoted **dissociation of UBL4A from BAG6**, implying that the BAG6–UBL4A–GET4 module is remodeled under proteotoxic conditions and may shift away from normal TA biogenesis (pqac-00000011, pqac-00000014). | Hagiwara et al. reported quantitative assays: co-IP with **n = 6** biological replicates analyzed by Student’s *t*-test; NanoBiT CCCP time-course **n = 3**, **P < 0.01**; CCCP 4 h assay **n = 4**, Welch’s *t*-test, **P < 0.01** (pqac-00000011). | Biochemical, cell assay, quantitative stress biology | Hagiwara 2023, *Biochem J*, doi: https://doi.org/10.1042/bcj20230267 |
| Related nuclear / DNA-damage context | The strongest direct evidence concerns **BAG6**, not GET4 as an autonomous nuclear factor. Because TRC35 controls BAG6 cytosolic retention, it indirectly interfaces with BAG6’s reported nuclear functions in **p300 acetylation**, **histone methylation**, and **DNA-damage signaling-mediated cell death**; however, direct GET4-specific nuclear signaling functions remain less established than its pretargeting role (pqac-00000009). | Mock 2017 explicitly ties TRC35 to BAG6 localization control while noting BAG6 nuclear functions; evidence is indirect for GET4 beyond localization control (pqac-00000009). | Structural, cell biology, literature synthesis | Mock 2017, *PNAS*, doi: https://doi.org/10.1073/pnas.1702940114 |
| 2023–2024 broader relevance / applications | Recent literature places GET4/TRC35-containing BAG6 complexes in broader **proteostasis surveillance**, including mitigation of aberrant noncoding translation products and maintenance of membrane protein biogenesis fidelity. One 2023 *Nature* study identified **BAG6, TRC35/GET4, RNF126, SGTA, and UBL4A** in this surveillance axis (pqac-00000008). Disease links in Open Targets are currently **association-level** rather than definitive mechanism-level annotations for GET4 itself (pqac-00000008). | Evidence supports translational quality control relevance but not yet a mature clinical application directly targeting GET4; Open Targets associations include neurodegenerative disease and congenital disorder of glycosylation type IIy, but these should be interpreted cautiously as evidence aggregation rather than causal proof (pqac-00000008). | Genetics / CRISPRi association, database aggregation | Kesner 2023, *Nature*, doi: https://doi.org/10.1038/s41586-023-05946-4 ; Open Targets context (pqac-00000008) |


*Table: This table summarizes the best-supported functions, interactions, localization, quality-control roles, and recent developments for human GET4/TRC35 (UniProt Q7L5D6). It emphasizes experimentally grounded mechanisms in tail-anchored protein targeting and distinguishes direct evidence from broader association-level disease links.*