Tetratricopeptide repeat protein 39C (TTC39C) of the crab-eating macaque, a non-catalytic member of the TTC39/IML2 family built around a TPR-like helical (Iml2-TPR_39) domain. The sequence corresponds to residues 39-583 of human TTC39C (99.6% identical over that span): the gene model starts at the human internal Met39 and lacks only the disordered N-terminal extension, so all annotated TPR repeats are present. Within PANTHER family PTHR31859 it falls in subfamily SF1 together with human, mouse, rat and zebrafish TTC39C (fungal IML2-like proteins also map to SF1 but sit outside the metazoan TTC39C clade). Functional knowledge of the orthologous group comes mainly from zebrafish ttc39c: morpholino knockdown, with mRNA rescue of the body-curvature phenotype, reduces the number and length of Kupffer's vesicle cilia and nearly abolishes pronephric cilia beating, and overexpressed TTC39C associates weakly with the IFT-A subunits IFT144 and IFT139, consistent with a role in assembling motile cilia, perhaps in connection with intraflagellar transport. The protein's subcellular localization in vertebrate cells, its direct binding partners and its molecular activity have not been determined. The paralog TTC39B (a different PANTHER subfamily) promotes ubiquitin-dependent degradation of LXR in liver, but that activity has not been shown for TTC39C.
Summary: TreeGrafter transfer from PANTHER node PTN001275231; the underlying PAINT assertion (IBD at PTN002840059, Euteleostomi) is seeded by zebrafish ttc39c (ZFIN:ZDB-GENE-050522-194) whose only evidence is the morphant phenotype of Xu et al. 2015 (PMID:25860617): more than 75% of ttc39c morphants had abnormal otoliths. The authors themselves present the otolith defect as a secondary ciliopathy phenotype that follows from loss of inner-ear cilia motility, not as a process the protein performs. Macaque A0A2K5UJ34 is the TTC39C ortholog (PANTHER SF1, file:MACFA/A0A2K5UJ34/A0A2K5UJ34-bioinformatics/RESULTS-rereview.md), so the phylogenetic placement is not in question; what is in question is whether the zebrafish observation is process participation at all.
Reason: Otolith morphogenesis here is an organismal readout downstream of defective motile cilia in a morpholino knockdown, the class of phenotype this review does not treat as process participation (the same logic by which the PAINT curator declined to propagate the zebrafish heart left/right asymmetry IMP from the same paper). No step of otolith formation is shown to be performed by TTC39C. In addition, primates form otoconia rather than the fused otoliths of teleosts, so the propagated term describes an anatomy the macaque lacks. The defensible part of the zebrafish data is captured by the cilium assembly annotation, which is retained.
Since proper otolith formation requires cilia motility in the inner ear, defects in the inner ear motile cilia often lead to abnormal otoliths, which are fused, mispositioned, or of wrong sizes or numbers [39]. We found that, similar to the ttc25 morphants, more than 75% of the morphants of ttc4, -9c, -36, and -39c developed abnormal otoliths at 72 hpf
Summary: TreeGrafter transfer from PANTHER node PTN001275231; the underlying PAINT assertion is an IBD at PTN001275223 (Eumetazoa) seeded by zebrafish ttc39c. Macaque A0A2K5UJ34 is the TTC39C ortholog: it is 99.6% identical to human TTC39C over residues 39-583 and is classified in the same PANTHER subfamily (PTHR31859:SF1) as zebrafish ttc39c, so it descends from the node that carries the assertion. The zebrafish evidence (PMID:25860617) is a cellular phenotype rather than an organismal one: ttc39c morphants showed reduced number and length of Kupffer's vesicle cilia and nearly paralysed pronephric cilia (5.6 Hz versus 42.2 Hz beat frequency), and the morphant body-curvature phenotype was rescued by MO-resistant ttc39c mRNA. Overexpressed mouse TTC39C co-precipitated weakly with IFT-A subunits IFT144 and IFT139, which links the protein to IFT machinery rather than only to a downstream readout.
Reason: The PAINT node placement is consistent with the subfamily assignment of this macaque ortholog, and the donor evidence is a direct measurement of cilium formation in the cells that build the cilium, supported by a biochemical association with IFT-A. The basis is a single morpholino study, with mRNA rescue shown for body curvature rather than for cilia length, and no mammalian loss-of-function data; cilium assembly is nonetheless the most specific process the evidence supports and the best current statement of the gene's role. The more specific motile-cilium terms are not added because the study does not separate an assembly defect from a motility defect.
We thus examined KV cilia in embryos at the 7-somite stage and found that both the number and length of the KV cilia were significantly reduced in the ttc morphants
macaque residue 1 aligns to human Met39 and the segment runs to the human C-terminus.
Core Functions
TTC39C is a non-catalytic TPR-domain protein required for the assembly of motile cilia, as shown by knockdown of the zebrafish ortholog in the same PANTHER subfamily, where Kupffer's vesicle cilia are fewer and shorter and pronephric cilia barely beat. Its weak association with the IFT-A subunits IFT144 and IFT139 suggests that it acts with intraflagellar transport, but its molecular activity, direct partners and subcellular localization are not known, so no molecular function or location is asserted.
We thus examined KV cilia in embryos at the 7-somite stage and found that both the number and length of the KV cilia were significantly reduced in the ttc morphants
Q: Does TTC39C localize to cilia or basal bodies in mammalian multiciliated cells, given that the only vertebrate study could not immunostain it and the C. elegans ciliary localization comes from a worm protein whose orthology to TTC39C is not established?
Q: Is the TTC39C association with IFT144/IFT139 direct, and does it reflect a role in IFT-A function or in axonemal dynein arm assembly, which the authors raised for the paralysed pronephric cilia?
Suggested Experiments
Experiment: Generate stable ttc39c mutants in zebrafish (or Ttc39c knockout mice) to test whether the morpholino cilia-length and motility phenotypes are reproduced, and image tagged TTC39C in multiciliated airway cells to determine its ciliary localization.
Experiment: Proximity labelling or reconstitution with purified IFT-A to test whether TTC39C binds IFT144 and IFT139 directly.
External Prediction Reviews
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
Macaque TTC39C ortholog (PANTHER PTHR31859:SF1). The single ProtNLM2 process prediction, heart left/right asymmetry, rests on one zebrafish ttc39c morpholino study in which randomized heart-tube orientation is reported as a secondary ciliopathy readout of defective Kupffer's vesicle cilia; it is neither established nor refuted for the macaque protein and is scored uncertain.
Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.
GO:0061371 determination of heart left/right asymmetryGO_BP
UNC — Uncertain Review score: 1/2
Prediction method: ProtNLM2 · Version: UniProt 2024_06 pilot
Review rationale: The target is the TTC39C ortholog (PANTHER subfamily SF1, the same subfamily as zebrafish ttc39c), and the term is absent from its GOA annotations, so the prediction would be novel. The only experimental support is the zebrafish morpholino screen of Xu et al. 2015 (PMID:25860617), in which more than 64% of ttc39c morphants had misoriented heart tubes; the authors attribute this, like the otolith and body-curvature defects, to reduced number and length of Kupffer's vesicle cilia. Motile cilia of the left-right organiser do participate in laterality determination, so the prediction is biologically plausible, but the evidence is a single knockdown study with no mammalian loss-of-function data, and the PANTHER PAINT assertions for PTHR31859 propagate only cilium assembly and otolith morphogenesis, not a laterality term. The merged gene review accepts cilium assembly as the supported process and removes the parallel organismal readout (otolith morphogenesis) as a downstream ciliopathy phenotype rather than process participation; the heart asymmetry phenotype is of the same kind. No PubMed record links TTC39C to laterality outside this screen. The evidence therefore neither establishes nor refutes heart left/right asymmetry determination for macaque TTC39C.
Supporting Evidence:
file:MACFA/A0A2K5UJ34/A0A2K5UJ34-uniprot.txt: "ID A0A2K5UJ34_MACFA Unreviewed; 545 AA. ... DR InterPro; IPR019412; IML2/TPR_39. ... DR PANTHER; PTHR31859:SF1; TETRATRICOPEPTIDE REPEAT PROTEIN 39C; 1."
PMID:25860617: "More than 64% of the morphants of ttc25, -36, and -39c showed misoriented heart tubes toward either the right or the middle side, indicating a randomized heart tube orientation"
PMID:25860617: "We thus examined KV cilia in embryos at the 7-somite stage and found that both the number and length of the KV cilia were significantly reduced in the ttc morphants"