Abstract
Appropriate regulation of autophagy is crucial for clearing toxic proteins from cells. Defective autophagy results in accumulation of toxic protein aggregates that detrimentally affect cellular function and organismal survival. Here, we report that the microRNA miR-1 regulates the autophagy pathway through conserved targeting of the orthologous Tre-2/Bub2/CDC16 (TBC) Rab GTPase-activating proteins TBC-7 and TBC1D15 in Caenorhabditis elegans and mammalian cells, respectively. Loss of miR-1 causes TBC-7/TBC1D15 overexpression, leading to a block on autophagy. Further, we found that the cytokine interferon-β (IFN-β) can induce miR-1 expression in mammalian cells, reducing TBC1D15 levels, and safeguarding against proteotoxic challenges. Therefore, this work provides a potential therapeutic strategy for protein aggregation disorders.
Highlights
The accumulation of toxic aggregation-prone proteins is a hallmark of multiple human disease states such as Huntington’s (HD), Parkinson’s (PD), Alzheimer’s (AD) and forms of motor neuron disease (Bosco et al, 2011)
Using two independently-derived mir-1 deletion alleles, mir-1 and mir-1(n4102), we found that loss of mir-1 increases Q40 accumulation in body wall muscle (BWM), without affecting Q40 expression levels (Figure 1B–D and Figure 1—figure supplement 1)
We found that mir-1 expression in BWM, but not in the pharynx or intestine, rescued the aberrant Q40 aggregation phenotype in mir-1 animals (Figure 1E), demonstrating that mir-1 acts cell autonomously to control Q40 accumulation. miRNAs predominantly regulate gene expression through imperfect base-pairing with target mRNA 30-untranslated regions (30UTRs), causing RNA instability and/or translational repression (Bartel, 2009; Lewis et al, 2005)
Summary
The accumulation of toxic aggregation-prone proteins is a hallmark of multiple human disease states such as Huntington’s (HD), Parkinson’s (PD), Alzheimer’s (AD) and forms of motor neuron disease (Bosco et al, 2011). Autophagy is a degradation system that involves sequestration of cytoplasmic proteins and organelles by double-layered membranes that form vesicles called autophagosomes. Due to the central role of autophagy in the removal of aggregation-prone proteins, a better understanding of mechanisms controlling autophagy is essential for the identification of novel therapeutic opportunities for multiple disease states. The nature of imperfect binding specificity means that a single miRNA can regulate a large number of mRNA targets involved in complex cellular processes, thereby tightly controlling genetic networks during development and in response to stress (Pocock, 2011).
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