Abstract
Mitochondria and peroxisomes are independent but functionally closely related organelles. A few proteins have been characterized as dual-organelle locating proteins with distinct or similar roles on mitochondria and peroxisomes. MARCH5 is a mitochondria-associated ubiquitin ligase best known for its regulatory role in mitochondria quality control, fission, and fusion. Here, we used a proximity tagging system, PUP-IT, and identified new interacting proteins of MARCH5. Our data uncover that MARCH5 is a dual-organelle locating protein that interacts with several peroxisomal proteins. PEX19 binds the transmembrane region on MARCH5 and targets it to peroxisomes. On peroxisomes, MARCH5 binds and mediates the ubiquitination of PMP70. Furthermore, we find PMP70 ubiquitination and pexophagy induced by mTOR inhibition are blocked in the absence of MARCH5. Our study suggests novel roles of MARCH5 on peroxisomes.
Highlights
Peroxisomes are essential metabolic organelles that play critical Mfn1 levels and regulating mitochondria and ER contacting sites roles in the metabolism of lipid and reactive oxygen species (ROS). (Park et al, 2014; Sugiura et al, 2013)
The other is that MARCH5 mediates PMP70 ubiquitination in Torin1-induced pexophagy
In another study addressing the role of MARCH5 in mitophagy, GFP was knocked in to fuse with the N-terminus of MARCH5 (Shiiba et al, 2021)
Summary
Peroxisomes are essential metabolic organelles that play critical Mfn levels and regulating mitochondria and ER contacting sites roles in the metabolism of lipid and reactive oxygen species (ROS). (Park et al, 2014; Sugiura et al, 2013). In the presence of WT MARCH5-Myc, protein levels of PMP70, catalase, and PEX13 reduced with Torin treatment (Fig. 8, A and B). Folimycin blocked the reduction of peroxisome number in po-MARCH5(R)–expressing cells (Fig. 9 B) These results suggest that peroxisomal MARCH5 but not mitochondrial MARCH5 is responsible for Torin1-induced pexophagy. In MARCH5 KO HeLa cells, the addition of rapalog significantly reduced peroxisome numbers (Fig. 9 E and Fig. S5 C), confirming that MARCH5 works upstream of peroxisome protein ubiquitination in pexophagy. MARCH5 can localize on peroxisomes via PEX19/ PEX3 and plays a role in Torin1-induced pexophagy by mediating the ubiquitination of PMP70 (Fig. 9 F)
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