tusc2b is one of two zebrafish co-orthologs of human TUSC2 (FUS1), a small (111-residue) N-myristoylated mitochondrial protein. It keeps the N-terminal myristoylation glycine and the acidic calcium-binding motif (DEDGDLAHEFYEE) that define the TUSC2 family. In mammals TUSC2 localizes to mitochondria and regulates mitochondrial calcium uptake and calcium-coupled mitochondrial parameters (membrane potential, reactive oxygen species, permeability transition), and Tusc2-deficient mice show chronic inflammation, autoimmunity and premature age-related pathologies. Nothing has been measured for the zebrafish protein. tusc2b is the main zygotic TUSC2 transcript, expressed from the blastula through larval stages, and is expressed more highly than tusc2a in most adult tissues, including muscle, liver and brain.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003674 molecular_function | ND GO_REF:0000015 | ACCEPT | Summary: Root molecular-function term with no-data evidence. Reason: No molecular activity has been measured for zebrafish Tusc2b, and even for mammalian TUSC2 the calcium-binding activity is inferred from a conserved motif and structural modeling rather than a direct binding assay. The ND row correctly states that the molecular function is unknown. Supporting Evidence: PMID:24328503 Based on putative calcium-binding and myristoyl-binding domains that we identified in Fus1, we explored our hypothesis that Fus1 regulates mitochondrial calcium handling and calcium-coupled processes. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial location propagated from mouse Tusc2. Reason: Mitochondrial localization is the best-established property of TUSC2 and depends on N-myristoylation. tusc2b keeps the myristoylation glycine and the calcium-binding motif exactly, so it sits inside the clade that inherited the location. Not yet imaged in zebrafish. Supporting Evidence: PMID:35181743 Also, myristoylation-deficient FUS1/TUSC2 loses its characteristic mitochondria/ER localization and its abilities to induce apoptosis and suppress tumor cell proliferation in vitro. file:DANRE/tusc2a/tusc2a-bioinformatics/RESULTS.md Both copies keep the myristoylation site and the exact calcium-binding motif. |
| GO:0006954 inflammatory response | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Inflammatory response propagated from mouse Tusc2, whose knockout shows chronic inflammation and an altered response to asbestos. Reason: The mouse evidence is a knockout phenotype: loss of Fus1 perturbs immune cell numbers and cytokine dynamics, which the authors attribute to disturbed mitochondrial homeostasis. TUSC2 acts on mitochondrial calcium handling within cells; it does not itself carry out steps of the inflammatory response, so this is a downstream consequence rather than participation. For zebrafish there are no immune data at all. The mitochondrial terms describe what the protein does. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN002693339 SOURCE WEAK OR INFERRED A different node from the one carrying the mitochondrial terms; seeded by the mouse knockout inflammation phenotype, which reflects a downstream consequence of mitochondrial dysfunction. MGI:MGI:1931086 · Tusc2 (mouse) SOURCE WEAK OR INFERRED Knockout mice show chronic inflammation and altered cytokine dynamics; the authors attribute this to disturbed mitochondrial homeostasis rather than a direct role of Tusc2 in the inflammatory response. Supporting Evidence: PMID:22513871 Untreated Fus1(-/-) mice had an ~eight-fold higher proportion of peritoneal granulocytes than Fus1(+/+) mice, pointing at ongoing chronic inflammation. PMID:24328503 Our findings suggest that Fus1 achieves its protective role in inflammation, autoimmunity, and cancer via the regulation of mitochondrial calcium and calcium-coupled parameters. |
| GO:0051881 regulation of mitochondrial membrane potential | IBA GO_REF:0000033 | ACCEPT | Summary: Regulation of mitochondrial membrane potential propagated from mouse Tusc2. Reason: Loss of Fus1 changes mitochondrial membrane potential together with calcium uptake and ROS in mouse cells. This is the closest existing term to the proposed core role (mitochondrial calcium handling) and the node is appropriate for a protein that keeps both functional motifs. Untested in zebrafish. Supporting Evidence: PMID:24328503 The reduced rate of mitochondrial calcium uptake in Fus1-deficient cells correlated with cytosolic calcium increase and dysregulation of calcium-coupled mitochondrial parameters, such as reactive oxygen species production PMID:22513871 Finally, we demonstrated Fus1-dependent basal and asbestos-induced changes in major mitochondrial parameters (ROS production, mitochondrial potential and UCP2 expression) in Fus1(-/-) immune cells and in Fus1-depleted cancer cells |
Loading supporting content…
Download this section (compressed HTML)Q: Do zebrafish Tusc2a and Tusc2b both localize to mitochondria, and do both need the N-terminal glycine for it?
Q: Is tusc2b's role as the main zygotic copy (with tusc2a mostly maternal) a partition of an ancestral profile? What does gar TUSC2 expression look like through development?
Q: Does either copy bind calcium through the conserved DEDGDLAHEFYEE motif?
Experiment: Make tusc2b, tusc2a and double mutants (including maternal-zygotic tusc2a); measure mitochondrial calcium uptake and membrane potential in embryonic cells with genetically encoded sensors.
Hypothesis: Both copies regulate mitochondrial calcium uptake.
Type: genetic interaction
Experiment: Rescue double-mutant mitochondrial phenotypes with either coding sequence, and with a Gly2Ala myristoylation mutant as a control.
Hypothesis: The proteins are interchangeable.
Type: cross-rescue
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)