MicroRNA 199a-5p Attenuates Retrograde Transport and Protects against Toxin-Induced Inhibition of Protein Biosynthesis

Abstract

Retrograde transport (RT) allows cells the retrieval of receptors and other cellular cargoes to the Golgi contributing to the maintenance of cellular homeostasis. This transport route is also commonly used by several bacterial toxins to exert their deleterious actions on eukaryotic cells. While the retrograde transport process has been well characterized, the contribution of microRNAs (miRNAs) in regulating this cellular transport mechanism remains unknown. Here, we identified that the intronic miRNA family, , coordinate genes regulating RT and endosome trafficking. We demonstrate that miR-199a-5p attenuates the expression of Vps26A, Rab9B and M6PR, thereby controlling RT from endosomes to Trans Golgi network (TGN). Importantly, we found that overexpression of Vps26A construct resistant to miR-199a-5p inhibitory action abrogates the effect of miR-199a-5p on RT. Finally, we demonstrate that miR-199-5p overexpression attenuates Shiga toxin (STx-1)-mediated inhibition of protein biosynthesis. In summary, our work identifies the first non-coding RNA that influences RT and reduces protein biosynthesis inhibition caused by bacterial toxins.

Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome

“…The second target, VPS26B, is a component of the core retromer complex. Defects in retromer function attenuate retrograde transport from endosomes to the trans-Golgi network 46,59 : this may induce GA structural and functional alterations as well as inappropriate sorting and recycling activities of endosomes that may lead to increased secretion, as demonstrated for cathepsin-D precursor 60 , and Aβ in Alzheimer's disease 61 .…”

miR-199a-5p Represses Protective Autophagy and Overcomes Chemoresistance by Directly Targeting DRAM1 in Acute Myeloid Leukemia

“…Very recently, Aranda et al also reported that miR-199a-5p overexpression inhibited the lysosome acidification and reduced autophagosomal degradation, which are a part of the mechanisms for miR-199a-5p to regulate retrograde transport and endolysosomal system in mammalian cells. Their results indicated miR-199a-5p as a negative regulator of autophagy [45]. Yet, the roles of both miR-199a-5p and autophagy in drug-resistant mechanisms of acute myeloid leukemia cells are still unclear.…”

Atrial Fibrillation in Heart Failure Is Associated with High Levels of Circulating microRNA-199a-5p and 22–5p and a Defective Regulation of Intracellular Calcium and Cell-to-Cell Communication

“…Since protein levels were only decreased by 20% whereas currents were almost abolished in the patched cells, we cannot exclude that these miRNAs may alter protein function not only by lowering its expression but also by altering its trafficking and/or the protein surface localization. In agreement with this, it has been shown that miR-199a can strongly influence intracellular trafficking by regulating genes that coordinate retrograde transport and endocytosis [ 29 , 30 ].…”