Hcmv-miR-UL148D regulates the staurosporine-induced apoptosis by targeting the Endoplasmic Reticulum to Nucleus signaling 1(ERN1)

Abstract

The propensity of viruses to co-opt host cellular machinery by reprogramming the host’s RNA-interference machinery has been a major focus of research, however, regulation of host defense mechanisms by virus-encoded miRNA, is an additional regulatory realm gaining momentum in the arena of host-viral interactions. The Human Cytomegalovirus (HCMV) miRNAs, regulate many cellular pathways alone or in concordance with HCMV proteins, thereby paving a conducive environment for successful infection in the human host. We show that HCMV miRNA, hcmv-miR-UL148D inhibits staurosporine-induced apoptosis in HEK293T cells. We establish that ERN1 mRNA is a bonafide target of hcmv-miR-UL148D and its encoded protein IRE1α is translationally repressed by the overexpression of hcmv-miR-UL148D resulting in the attenuation of apoptosis. Unlike the host microRNA seed sequence (6–8 nucleotides), hcmv-miR-UL148D has long complementarity to 3’ UTR of ERN1 mRNA resulting in mRNA degradation. The repression of IRE1α by the hcmv-miR-UL148D further downregulates Xbp1 splicing and c-Jun N-terminal kinase phosphorylation thus regulating ER-stress and ER-stress induced apoptotic pathways. Strikingly, depletion of ERN1 attenuates staurosporine-induced apoptosis which further suggests that hcmv-miR-UL148D functions through regulation of its target ERN1. These results uncover a role for hcmv-miR-UL148D and its target ERN1 in regulating ER stress-induced apoptosis.

Sargassum polysaccharide attenuates osteoarthritis in rats and is associated with the up-regulation of the ITGβ1-PI3K-AKT signaling pathway

“…Among the potential targets identified, we consider ERN1, ATF4, BID and FAS worthy of further attention. Regarding ERN1, research indicates that ERN1 mRNA is the actual target of hcmv-miR-UL148D and its encoded protein IRE1α is translationally repressed by the overexpression of hcmv-miR-UL148D resulting in the attenuation of apoptosis [ 72 ]. Regarding ATF4, research has demonstrated that activated transcription factor 4 (ATF4) plays a pivotal role as the key transcription factor in ERS [ 73 ], and is at least partially implicated in ERS-mediated apoptosis [ 74 ].…”

MicroRNAs: Small but Key Players in Viral Infections and Immune Responses to Viral Pathogens

“…When canonically binding to the 3′UTR, they typically destabilize the transcript and trigger the degradation pathway of cellular mRNAs [69]. v-miRs have also been shown to bind to the 5′UTR, preventing translation without altering mRNA levels in the cell [70,71]. Alternatively, v-miRs binding to the 5′UTR can increase mRNA stability, preventing degradation and upregulating gene expression [14,72].…”

“…The use of miRNA gives viruses the ability to control gene expression and manipulate host cell activities to their benefit. miRNAs have been implicated in many processes during infection, including viral entry, viral replication, latency and reactivation, immune evasion, immune suppression or overactivation, inflammation, host cell survival, tumorigenesis, and more [10,13,14,43,[69][70][71]77,[80][81][82][85][86][87][88][89][90][91][92][93][94][95][96][97][98]. See Tables 1 and 2 for recent research developments in miRNA regulation of viral infection.…”

“…In addition, the outcome of these interactions should be confirmed at the cellar and organismal level. For example, miR-mRNA interactions predicted to decrease gene expression by degradation of mRNA should reflect this in both attenuated mRNA transcript levels and reduced protein output [70]. Furthermore, researchers may consider expanding on the local or systemic effects of viral miRNA packaged into exosomes and virus-induced changes in exosomal host miRNA levels [10,83,103].…”