Abstract
Viral infections lead to the death of more than a million people each year around the world, both directly and indirectly. Viruses interfere with many cell functions, particularly critical pathways for cell death, by affecting various intracellular mediators. MicroRNAs (miRNAs) are a major example of these mediators because they are involved in many (if not most) cellular mechanisms. Virus-regulated miRNAs have been implicated in three cell death pathways, namely, apoptosis, autophagy, and anoikis. Several molecules (e.g., BECN1 and B cell lymphoma 2 [BCL2] family members) are involved in both apoptosis and autophagy, while activation of anoikis leads to cell death similar to apoptosis. These mechanistic similarities suggest that common regulators, including some miRNAs (e.g., miR-21 and miR-192), are involved in different cell death pathways. Because the balance between cell proliferation and cell death is pivotal to the homeostasis of the human body, miRNAs that regulate cell death pathways have drawn much attention from researchers. miR-21 is regulated by several viruses and can affect both apoptosis and anoikis via modulating various targets, such as PDCD4, PTEN, interleukin (IL)-12, Maspin, and Fas-L. miR-34 can be downregulated by viral infection and has different effects on apoptosis, depending on the type of virus and/or host cell. The present review summarizes the existing knowledge on virus-regulated miRNAs involved in the modulation of cell death pathways. Understanding the mechanisms for virus-mediated regulation of cell death pathways could provide valuable information to improve the diagnosis and treatment of many viral diseases.
Highlights
Virus infections have long posed a threat to human public health
Viral pathogens are a major threat to public health, either by directly causing viral infections or being responsible for several cancer types
One of the most critical cell functions affected by viruses is programmed cell death, which has repeatedly been shown to be mediated by several miRNAs. miRNA-dependent regulation of cell death pathways has proved to be a complex yet crucial issue, with more and more miRNAs having been found to be involved in both positive and negative regulation of these pathways
Summary
Virus infections have long posed a threat to human public health. virus-related deaths have sharply declined during the past century,[1] the death toll is still relatively high. Defects in the regulation of apoptosis (either too little or too much) are involved in several human diseases, such as neurodegenerative conditions, ischemic tissue damage, autoimmune disorders, and in numerous types of cancer.[24] Slattery et al.[22] described the involvement of multiple miRNAs in the process of apoptosis, both in the intrinsic and extrinsic pathways through regulating the expression of specific genes (extrinsic pathway genes CASP7 and BIRC5, and intrinsic pathway genes CSF2RB and BCL2) in colorectal cancer In another similar study, some apoptosis-associated genes, including BCL2 and PUMA (a Bcl-2 family member), were found to be regulated by various miRNAs, such as miR-148a, miR-125b, miR-143, and miR-203.78–81 miRNAs have been reported to regulate other targets in apoptosis-related pathways, such as PEG10, BTG1, ID1, interleukin (IL)-32, and NCF2.82. Flaviviruses, which are single-stranded (ss)-positive RNA viruses, interfere with the miRNA processing machinery by allowing the accumulation of the non-coding (nc) subgenomic flavivirus RNA (sfRNA) that carries out sequestration of the double-stranded RNA (dsRNA)
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