MTRNR2L5

Summary: Electronic mapping of UniProt's Secreted subcellular-location line for P0CJ72. That line is itself annotated ECO:0000250 by similarity to humanin (UniProtKB:Q8IVG9), so the row carries no observation made on MTRNR2L5.

Reason: MTRNR2L5 is known only as a transcript (UniProt protein existence level 2); no peptide from this locus has been detected in any compartment, by mass spectrometry or otherwise. UniProt's Secreted and Cytoplasm lines for P0CJ72 are themselves ECO:0000250 by-similarity statements transferred from humanin (file:human/MTRNR2L5/MTRNR2L5-uniprot.txt), so both the ISS row (donor UniProtKB:Q8IVG9) and the subcellular-location IEA row state the same humanin claim, once directly and once via the controlled-vocabulary mapping. Secretion of humanin is not a generic property of the sequence: it depends on Leu9-Leu11 and on Pro19-Val20 [PMID:35372353], and Bodzioch et al. proposed on the alignment that position 19 is what decides whether a nuclear isoform is secreted at all [PMID:19477263]. In MTRNR2L5, Leu9-Leu11 and Pro19 are intact; Val20 is replaced by methionine within the Pro19-Val20 secretion segment. The claim may well be right if the peptide exists, so I mark it as an over-annotation rather than removing it: what is wrong is that it is asserted of this locus on the strength of humanin alone.

Summary: Curator transfer of humanin's secreted location to MTRNR2L5 on sequence similarity. Humanin's own extracellular annotations are IDA/EXP from several studies, so the donor side is sound; the question is only whether the transfer is safe.

Reason: MTRNR2L5 is known only as a transcript (UniProt protein existence level 2); no peptide from this locus has been detected in any compartment, by mass spectrometry or otherwise. UniProt's Secreted and Cytoplasm lines for P0CJ72 are themselves ECO:0000250 by-similarity statements transferred from humanin (file:human/MTRNR2L5/MTRNR2L5-uniprot.txt), so both the ISS row (donor UniProtKB:Q8IVG9) and the subcellular-location IEA row state the same humanin claim, once directly and once via the controlled-vocabulary mapping. Secretion of humanin is not a generic property of the sequence: it depends on Leu9-Leu11 and on Pro19-Val20 [PMID:35372353], and Bodzioch et al. proposed on the alignment that position 19 is what decides whether a nuclear isoform is secreted at all [PMID:19477263]. In MTRNR2L5, Leu9-Leu11 and Pro19 are intact; Val20 is replaced by methionine within the Pro19-Val20 secretion segment. An ISS asserts that the donor observation holds for the target; here the premise that a peptide exists at all is untested, so the row over-reaches.

Summary: Electronic mapping of UniProt's Cytoplasm line, which is itself a by-similarity statement transferred from humanin.

Reason: MTRNR2L5 is known only as a transcript (UniProt protein existence level 2); no peptide from this locus has been detected in any compartment, by mass spectrometry or otherwise. UniProt's Secreted and Cytoplasm lines for P0CJ72 are themselves ECO:0000250 by-similarity statements transferred from humanin (file:human/MTRNR2L5/MTRNR2L5-uniprot.txt), so both the ISS row (donor UniProtKB:Q8IVG9) and the subcellular-location IEA row state the same humanin claim, once directly and once via the controlled-vocabulary mapping. A translated 24-28-residue peptide would plausibly be cytosolic, which is why this row is the least objectionable of the four; but it is asserted from humanin, not observed here, and it adds nothing to the record of this locus.

Summary: Curator transfer of humanin's cytoplasmic location on sequence similarity; humanin's own cytoplasm annotations are IDA/EXP.

Reason: MTRNR2L5 is known only as a transcript (UniProt protein existence level 2); no peptide from this locus has been detected in any compartment, by mass spectrometry or otherwise. UniProt's Secreted and Cytoplasm lines for P0CJ72 are themselves ECO:0000250 by-similarity statements transferred from humanin (file:human/MTRNR2L5/MTRNR2L5-uniprot.txt), so both the ISS row (donor UniProtKB:Q8IVG9) and the subcellular-location IEA row state the same humanin claim, once directly and once via the controlled-vocabulary mapping. A translated 24-28-residue peptide would plausibly be cytosolic, which is why this row is the least objectionable of the four; but it is asserted from humanin, not observed here, and it adds nothing to the record of this locus.

Summary: Phylogenetic propagation of humanin's receptor antagonist activity to MTRNR2L5 from the humanin-family node PANTHER:PTN002141596. The grounding experiment is humanin competing with amyloid-beta at FPRL1 [PMID:15153530]; nothing comparable has been done with HN5.

Reason: The IBD behind this row places the activity at the humanin-family node, and the placement is reasonable for the mitochondrial peptide: humanin is a genuine FPRL1 ligand and the antagonism of amyloid-beta at that receptor is directly observed [PMID:15153530]. Arguing with the row means asking whether MTRNR2L5 sits inside the clade that inherited the function, and the difficulty is that the question is not really phylogenetic. The nuclear MT-RNR2-like loci are copies of a mitochondrial rRNA segment, so descent in this tree tracks genomic sequence rather than a protein-coding lineage, and membership of the node does not establish that the ORF is translated, that the peptide is stable, or that it reaches a receptor. On residues: HN5 keeps Thr13 and Ser14 and is the one nuclear humanin-like peptide that has been synthesised and assayed: the wild-type peptide is cytoprotective against staurosporine-induced apoptosis and the common Thr13->Ile variant (dbSNP rs11004928) is less so [PMID:19477263]. Bodzioch et al., who defined these loci, singled out position 13 as the one that may matter for cell-surface receptor binding [PMID:19477263]. A second, term-level point applies to every member of this node: receptor antagonist activity describes humanin's competition with amyloid-beta at FPRL1, which is a property measured in a specific assay, whereas humanin also carries receptor ligand activity by IDA - so even for the donor the term captures one facet of the interaction. The node placement is defensible and the row may yet prove right, so this is an over-annotation rather than an error: it states an activity for a gene product that has never been shown to exist, let alone to engage a receptor.

Summary: Phylogenetic propagation of negative regulation of the execution phase of apoptosis from the humanin-family node. The donor listed alongside the node is P0CJ72 itself - this locus - which carries its own IMP for the same term from [PMID:19477263].

Reason: This is the one row of the seven-gene set where the IBA has experimental grounding on the target itself. MTRNR2L5 appears in its own WITH/FROM because its IMP annotation is one of the descendant evidences the PAINT curator used to place the IBD, which is the expected pattern and not circularity. The underlying experiment is the one functional assay ever performed on a nuclear humanin-like sequence: synthetic HN5 peptide protects cells from staurosporine-induced apoptosis, and the common Thr13->Ile variant protects less well [PMID:19477263]. I accept the row on the strength of that, while recording the real limitation - the assay tested a synthesised peptide, so it establishes what the HN5 sequence can do and not that the locus produces it in vivo.

Summary: UniProt curation of the Bodzioch data: MTRNR2L5 transcript falls 6 h and rises 24 h after staurosporine treatment, and synthetic HN5 peptide protects cells against staurosporine-induced apoptosis.

Reason: Two different observations stand behind this row and they differ in strength. That the transcript changes level after staurosporine [PMID:19477263] is regulation of the gene, which on its own is thin support for involvement in a cellular response. The stronger part is that the synthetic HN5 peptide actively limits staurosporine-induced death [PMID:19477263], which is participation rather than mere responsiveness. I keep the term on that basis but mark it non-core: staurosporine is a laboratory kinase inhibitor, so the term records the assay in which the activity was seen rather than a physiological role, and the physiologically meaningful statement is the apoptosis term.

Summary: UniProt curation from the same study. The cached record for PMID:19477263 is abstract-only and the abstract reports cytoprotection against staurosporine-induced apoptosis without mentioning mitochondrial membrane permeability or any mitochondrial readout.

Reason: I cannot adjudicate this row. The curator who made it had the full text, which is not in the publication cache here, and mitochondrial outer-membrane permeabilisation is the standard readout in staurosporine apoptosis experiments, so a cytochrome c release or membrane-potential measurement on HN5-treated cells is entirely plausible and would support the term directly. It is also the most mechanistically specific claim made about any nuclear humanin-like peptide, and it is not derivable from the abstract. Following the rule for unverifiable experimental annotations, I leave it UNDECIDED rather than guess: resolving it needs the figure in which permeability was measured, and whether it was measured with HN5 or with humanin.

Summary: UniProt experimental annotation from the HN5 cytoprotection assay: synthetic wild-type HN5 peptide reduces staurosporine-induced apoptosis, and the Thr13->Ile variant peptide (dbSNP rs11004928) does so less effectively.

Reason: This is the only experimentally grounded functional annotation on any of MTRNR2L1-7, and it is the reason MTRNR2L5 is the donor for the family-wide IBA rows. The assay is informative in both directions: the wild-type peptide protects, and a single natural substitution at position 13 reduces protection, which is a structure-activity result rather than a bare phenotype [PMID:19477263]. I accept it, with the caveat that the experiment establishes an activity of the HN5 sequence as a synthetic peptide and does not show that the MTRNR2L5 locus produces that peptide in cells - the gap that runs through this whole gene family. The evidence code IMP is generous for a synthetic-peptide experiment, but the cached record is abstract-only, so whether cells were also manipulated for MTRNR2L5 expression cannot be checked here.