MicroRNAs miR-19, miR-340, miR-374 and miR-542 regulate MID1 protein expression
Fig 6
Model showing the role of MID1 in diverse diseases.
We identified miRNAs hsa-miR-374a-5p, hsa-miR-542-3p, hsa-miR-19b-3p, and hsa-miR-340-5p as regulators of MID1. By controlling the expression levels of MID1 these miRNAs may affect several MID1-dependent processes. Functionally, MID1 acts as E3 ubiquitin ligase. Known targets of MID1’s ubiquitin ligase activity include PP2A and Fu. By catalyzing the ubiquitination PP2A MID1 induces the proteasomal degradation of PP2A, thereby reducing PP2A activity towards its target proteins. These include proteins involved in transcription regulation of inflammatory genes via NF-κB signaling, which are essentially involved in chronic inflammatory diseases such as asthma or eosinophilic oesophagitis, as well as the Tau protein, that is important in Alzheimer’s disease. Besides inhibiting PP2A MID1 stimulates the activity of mTOR. PP2A and mTOR regulate phosphorylation and thereby activity of the translational regulator S6K. Via PP2A and mTOR, MID1 controls translation of its target mRNAs. These include APP and BACE1, which play an important role in Alzheimer’s disease, mutant HTT, which causes Huntington’s disease, as we as that androgen receptor (AR), which is involved in prostate cancer. The second known target of MID1’s ubiquitin ligase activity is the kinase Fu. Upon MID1-dependent ubiquitination, this protein gets cleaved, which produces an active truncated protein that regulates the transcription factor GLI3.