Next, we observed that the SSG-mutated form of ZNRF3 not only blocked β-TRCP-shortened ZNRF3 half-life, but also decreased CKIδ-mediated turnover of ZNRF3 (Figs. 4E, 4F, S4A, and S4B).
Our findings are consistent with the model that the PINK1/Parkin pathway promotes the ubiquitin-mediated turnover of dMfn.
The subsequent ubiquitin-mediated turnover of dMfn would then inhibit mitochondrial fusion, and thus promote mitochondrial fragmentation (Figure 5).
These pathfinding and fasciculation defects reflect what we suspect: Ppt1-mediated turnover of palmitoylated developmental proteins is necessary throughout development such that its loss is cumulative and progressive.
To determine if RPM-1 is required for the ubiquitin-mediated turnover of GLR-1, we introduced nuIs89 into lin-10 mutants, rpm-1 mutants, and rpm-1 lin-10 double mutants.
We identified ScDDI1-like, a UbL-UbA protein involved in the MEC1/ATR-mediated turnover of an F-box protein [121], hPSO4, or IBR-RINGs, indicating a regulation of nucleic acid metabolism.
Our finding that the abundance of dMfn is increased in PINK1 and parkin mutants and decreased upon overexpression of PINK1 and Parkin is consistent with the hypothesis that PINK1 and Parkin promote the ubiquitin-mediated turnover of dMfn.
Our findings suggest that dMfn is a direct substrate of the PINK1/Parkin pathway and that the mitochondrial morphological alterations and tissue degeneration phenotypes that derive from mutations in PINK1 and parkin result at least in part from reduced ubiquitin-mediated turnover of dMfn.
To test the hypothesis that Parkin promotes the ubiquitin-mediated turnover of core components of the mitochondrial morphogenesis machinery, we sought to explore the effects of altered Parkin activity on the steady-state abundance of the mitochondrial fission-promoting factor Drp1 and the mitochondrial fusion-promoting factors Opa1 and dMfn.
Together, our findings suggest that dMfn is a direct substrate of PINK1 and Parkin, and that the effects of reduced PINK1 and Parkin activity on mitochondrial morphology and tissue integrity derive at least in part from reduced ubiquitin-mediated turnover of dMfn.
(143) Proteomics was employed to reveal an important novel function for p97 in ubiquitin proteasome-mediated tubiquitin proteasome-mediated
