MEK5/ERK5-Mediated Regulation of Mitophagy
Jane E. Craig1,2, Raju Rayavarapu1, Wei Zhuang1, Malia Potts1
1St. Jude Children's Research Hospital; 2University of Tennessee Health Science Center
Mitochondrial turnover protects against neurodegenerative and autoimmune diseases. Impaired mitochondrial turnover has also been implicated in cancer through mitochondrial derived reactive oxygen species and increased risk of mtDNA mutations. Selective degradation of mitochondria by autophagy, or mitophagy, removes damaged and dysfunctional mitochondria to protect against such diseases. Selective autophagy utilizes adaptor proteins like p62 or autophagy receptors like NIX to ensure only mitochondria that have been tagged for destruction are delivered to the lysosome and degraded.
Utilizing FUSION (Functional Signature-based Ontology), we have identified the MEK5/ERK5 signaling pathway as a novel regulator of mitophagy. We find that pharmacological inhibition or genetic disruption of the MEK5/ERK5 pathway results in increased mitochondrial accumulation and decreased mitophagy as detected via mito-mKeima. Additionally, MEK5/ERK5 inhibition causes p62 to accumulate and alters its pattern of posttranslational modifications. Most notably, we observe a decrease in p62 phosphorylation at a putative TBK1 phosphorylation site upon MEK5 inhibition. TBK1 is a kinase that promotes selective autophagy through activation of specific autophagy adaptor proteins. We find that phosphorylated (i.e. activated) TBK1 physically associates with ERK5, and that inhibition of ERK5 reduces TBK1 phosphorylation. We hypothesize that MEK5 and ERK5 induce mitophagy by bringing p62 and active TBK1 together to drive TBK1-mediated phosphorylation of p62, thus activating p62 to function as an adaptor for selective mitophagy.
