SMIM14 (formerly C4orf34) is a 99-amino-acid (about 10.7 kDa) single-pass membrane protein of the endoplasmic reticulum, conserved across vertebrates (Pfam DUF2615). Its single transmembrane helix (residues 50-70) is internal, with no cleavable signal peptide; the 49-residue N-terminal segment faces the ER lumen and the short proline-rich C-terminal tail faces the cytosol. Tagged SMIM14 co-localises with the ER markers calnexin and Sec61 and is retained in the ER by its transmembrane segment, as it carries no canonical ER retention motif. The mouse transcript is found in all tissues examined, and in human the transcript is most abundant in liver and hepatocytes. SMIM14 expression is not induced by tunicamycin-triggered ER stress. No molecular activity or biological process has been demonstrated; the reported interactions are yeast two-hybrid hits without functional follow-up.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | REMOVE | Summary: Yeast two-hybrid interaction with FATE1, from a method-development screen (Stitch-seq). Reason: Bare protein binding carries no functional information, and no more informative molecular function can be supported. The SMIM14-FATE1 pair is recovered in two independent yeast two-hybrid screens (this one and HuRI) and is compartment-compatible, since FATE1 is an ER/mitochondria membrane protein, but its functional meaning has not been tested. Removal does not imply that the interaction is false. Supporting Evidence: PMID:21516116 test the strategy in a high-throughput yeast two-hybrid (Y2H) system |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI yeast two-hybrid interaction with SGTA, a cytosolic co-chaperone that binds hydrophobic membrane-protein segments. Reason: Bare protein binding carries no functional information. SGTA recognises exposed hydrophobic transmembrane segments of client membrane proteins, so pairing with a single-pass protein expressed in the yeast nucleus is expected regardless of SMIM14 function, and says nothing about what SMIM14 does. Supporting Evidence: PMID:32296183 We screened this search space a total of nine times with a panel of three Y2H assay versions |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI yeast two-hybrid interaction with SLPI, a secreted protease inhibitor. Reason: Bare protein binding carries no functional information. SLPI is a secreted protein and SMIM14 is an ER-resident membrane protein, so a physiological interaction is unlikely outside the secretory lumen, and none has been tested. Removal does not imply that the screen result is wrong. Supporting Evidence: PMID:32296183 We screened this search space a total of nine times with a panel of three Y2H assay versions |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI yeast two-hybrid interaction with TMEM42, an uncharacterised multi-pass membrane protein. Reason: Bare protein binding carries no functional information, and neither partner has a known function from which a more informative term could be derived. Supporting Evidence: PMID:32296183 We screened this search space a total of nine times with a panel of three Y2H assay versions |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI yeast two-hybrid interaction with FATE1, reproducing the earlier Stitch-seq result. Reason: Bare protein binding carries no functional information, and no more informative molecular function can be supported. This is the only SMIM14 interaction reported twice, and it is compartment-compatible, which makes it the best candidate for follow-up rather than a basis for annotation. Supporting Evidence: PMID:32296183 We screened this search space a total of nine times with a panel of three Y2H assay versions |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Yeast two-hybrid interaction with SPRED1, a plasma-membrane-associated negative regulator of Ras-MAPK signalling, from a neurodegeneration-focused screen. Reason: Bare protein binding carries no functional information. A single unconfirmed yeast two-hybrid hit with no functional follow-up does not support a role for SMIM14 in MAPK signalling. Supporting Evidence: PMID:32814053 generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assertion that SMIM14-family proteins reside in the ER, seeded by the experimental annotation of human SMIM14 itself. Reason: Consistent with the direct localisation data. SMIM14 appearing in its own WITH/FROM is expected: its IDA annotation is the descendant evidence the PAINT curator used, and the IBA adds the claim that ER residence is shared across the family. |
| GO:0005783 endoplasmic reticulum | IDA PMID:24499674 Characterization of the cellular localization of C4orf34 as ... | ACCEPT | Summary: Tagged SMIM14 co-localises with the ER markers calnexin and Sec61 in HeLa and HEK293T cells, and its transmembrane segment is sufficient for ER retention. Reason: Directly supported by two independent ER markers and by deletion mapping. The evidence uses overexpressed tagged constructs rather than endogenous protein, but is consistent with the predicted topology and with the IBA. The more specific ER membrane term (GO:0005789) is also annotated. Supporting Evidence: PMID:24499674 hC4orf34-EGFP was co-localized with endogenous calnexin (Fig. 2B), suggesting ER targeting of hC4orf34-EGFP. PMID:24499674 Human hC4orf34-3xFLAG was co-localized with Sec61-EGFP (Fig. 2B), further confirming the ER localization of hC4orf34-3xFLAG. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic mapping of the UniProt subcellular location "Endoplasmic reticulum membrane; Single-pass membrane protein", which UniProt grounds in PMID:24499674. Reason: The most specific correct location. ER residence and membrane insertion with a lumenal N terminus were both shown experimentally. Supporting Evidence: PMID:24499674 These results suggested that the N-terminus of hC4orf34 might be localized at the luminal side of the ER |
Loading supporting content…
Download this section (compressed HTML)Q: Is the SMIM14-FATE1 interaction, recovered in two independent yeast two-hybrid screens, detectable between the endogenous proteins, and does it place SMIM14 at ER-mitochondria contact sites?
Q: Given its high expression in hepatocytes, does SMIM14 loss affect any hepatic ER function such as lipoprotein secretion, lipid synthesis or Ca2+ handling?
Experiment: Co-immunoprecipitate endogenous SMIM14 and FATE1 from a cell line expressing both, and compare the distribution of endogenously tagged SMIM14 between bulk ER and mitochondria-associated membranes by fractionation and proximity ligation.
Hypothesis: SMIM14 is enriched at ER-mitochondria contact sites through FATE1.
Experiment: Delete SMIM14 in hepatocyte-derived cells (HepG2, or primary or iPSC-derived hepatocytes) and measure ER Ca2+ stores, unfolded protein response markers, triglyceride and apolipoprotein B secretion, and cholesterol synthesis.
Hypothesis: SMIM14 contributes to a hepatocyte ER function.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)