Ribosomal protein L22 inhibits regulation of cellular activities by the Epstein‐Barr virus small RNA EBER‐1

Abstract

Epstein-Barr virus (EBV) is a potent mitogenic and antiapoptotic agent for B lymphocytes and is associated with several different types of human tumour. The abundantly expressed small viral RNA, EBER-1, binds to the growth inhibitory and pro-apoptotic protein kinase R (PKR) and blocks activation of the latter by double-stranded RNA. Recent evidence has suggested that expression of EBER-1 alone in EBV-negative B cells promotes a tumorigenic phenotype and that this may be related to inhibition of the proapoptotic effects of PKR. The ribosomal protein L22 binds to EBER-1 in virus-infected cells, but the significance of this has not previously been established. We report here that L22 and PKR compete for a common binding site on EBER-1. As a result of this competition, L22 interferes with the ability of the small RNA to inhibit the activation of PKR by dsRNA. Transient expression of EBER-1 in murine embryonic fibroblasts stimulates reporter gene expression and partially reverses the inhibitory effect of PKR. However, EBER-1 is also stimulatory when transfected into PKR knockout cells, suggesting an additional, PKR-independent, mode of action of the small RNA. Expression of L22 prevents both the PKR-dependent and -independent effects of EBER-1 in vivo. These results suggest that the association of L22 with EBER-1 in EBV-infected cells can attenuate the biological effects of the viral RNA. Such effects include both the inhibition of PKR and additional mechanism(s) by which EBER-1 stimulates gene expression.

Whole-exome sequencing association study reveals genetic effects on tumor microenvironment components in nasopharyngeal carcinoma

“…We found that the NPC-associated variant rs2276868 modulates RPL14 expression through the TF NKRF , an inhibitor of the NF-κB pathway involved in NPC development, ( 31 ). Our findings further demonstrate that RPL14 suppresses the EBV life cycle in NPC, consistent with the reported role of other RPL family members in EBV regulation ( 32 ). Given the critical role of uncontrolled EBV activity in NPC development ( 33 ), it is plausible that RPL14 , with its ability to inhibit EBV activity, plays a key role in repressing tumorigenesis.…”

Whole-exome sequencing association study reveals genetic effects on tumor microenvironment components in nasopharyngeal carcinoma

“…We found that the NPC-associated variant rs2276868 modulates RPL14 expression through the TF NKRF , an inhibitor of the NF-κB pathway involved in NPC development, ( 31 ). Our findings further demonstrate that RPL14 suppresses the EBV life cycle in NPC, consistent with the reported role of other RPL family members in EBV regulation ( 32 ). Given the critical role of uncontrolled EBV activity in NPC development ( 33 ), it is plausible that RPL14 , with its ability to inhibit EBV activity, plays a key role in repressing tumorigenesis.…”

Leukemia virus long terminal repeat activates NFκB pathway by a TLR3-dependent mechanism

“…Comparison of GFP expression in these three cells showed that transfection efficiency in PKR −/− cells were 40-50%, compared to 25-30% in Balb-3T3 cells and 15-20% in PKR +/+ MEFs. Lower transfection efficiency in PKR +/+ MEFs compared to PKR −/− lines has also been reported in other studies (Elia et al, 2004). These results demonstrated that PKR is not necessary for NF B activation by the LTR.…”

Large-Scale Whole-Exome Sequencing Association Study Implicates Genetic Effects on Viral Oncogenesis and Tumor Microenvironment in Nasopharyngeal Carcinoma

“…Single-cell transcriptomic analyses revealed an inverse association between RPL14 expression and EBV activity in malignant NPC cells, which is further corroborated by the suppressive effect of RPL14 on EBV infection and lytic cycle in NPC cells. Given the involvement of RPL22 45 and RPL4 46 , both of which belong to the same RPL family as RPL14 47 , in EBV infection, these findings highlight the crucial role of RPL family members in EBV life cycle. Furthermore, our study revealed that RPL14 inhibits NPC tumorigenesis, consistent with its tumor-suppressive function reported in an in vitro NPC study 48 and in other cancer types 49 .…”

Whole-exome sequencing association study reveals genetic effects on tumor microenvironment components in nasopharyngeal carcinoma

“…We found that the NPC-associated variant rs2276868 modulates RPL14 expression through the TF NKRF , an inhibitor of the NF-κB pathway involved in NPC development, ( 31 ). Our findings further demonstrate that RPL14 suppresses the EBV life cycle in NPC, consistent with the reported role of other RPL family members in EBV regulation ( 32 ). Given the critical role of uncontrolled EBV activity in NPC development ( 33 ), it is plausible that RPL14 , with its ability to inhibit EBV activity, plays a key role in repressing tumorigenesis.…”

Leukemia virus long terminal repeat activates NFκB pathway by a TLR3-dependent mechanism

“…Comparison of GFP expression in these three cells showed that transfection efficiency in PKR −/− cells were 40-50%, compared to 25-30% in Balb-3T3 cells and 15-20% in PKR +/+ MEFs. Lower transfection efficiency in PKR +/+ MEFs compared to PKR −/− lines has also been reported in other studies (Elia et al, 2004). These results demonstrated that PKR is not necessary for NF B activation by the LTR.…”

Large-Scale Whole-Exome Sequencing Association Study Implicates Genetic Effects on Viral Oncogenesis and Tumor Microenvironment in Nasopharyngeal Carcinoma

“…Single-cell transcriptomic analyses revealed an inverse association between RPL14 expression and EBV activity in malignant NPC cells, which is further corroborated by the suppressive effect of RPL14 on EBV infection and lytic cycle in NPC cells. Given the involvement of RPL22 45 and RPL4 46 , both of which belong to the same RPL family as RPL14 47 , in EBV infection, these findings highlight the crucial role of RPL family members in EBV life cycle. Furthermore, our study revealed that RPL14 inhibits NPC tumorigenesis, consistent with its tumor-suppressive function reported in an in vitro NPC study 48 and in other cancer types 49 .…”

Whole-exome sequencing association study reveals genetic effects on tumor microenvironment components in nasopharyngeal carcinoma

“…We found that the NPC-associated variant rs2276868 modulates RPL14 expression through the TF NKRF , an inhibitor of the NF-κB pathway involved in NPC development, ( 31 ). Our findings further demonstrate that RPL14 suppresses the EBV life cycle in NPC, consistent with the reported role of other RPL family members in EBV regulation ( 32 ). Given the critical role of uncontrolled EBV activity in NPC development ( 33 ), it is plausible that RPL14 , with its ability to inhibit EBV activity, plays a key role in repressing tumorigenesis.…”

Leukemia virus long terminal repeat activates NFκB pathway by a TLR3-dependent mechanism

“…Comparison of GFP expression in these three cells showed that transfection efficiency in PKR −/− cells were 40-50%, compared to 25-30% in Balb-3T3 cells and 15-20% in PKR +/+ MEFs. Lower transfection efficiency in PKR +/+ MEFs compared to PKR −/− lines has also been reported in other studies (Elia et al, 2004). These results demonstrated that PKR is not necessary for NF B activation by the LTR.…”

Large-Scale Whole-Exome Sequencing Association Study Implicates Genetic Effects on Viral Oncogenesis and Tumor Microenvironment in Nasopharyngeal Carcinoma

“…Single-cell transcriptomic analyses revealed an inverse association between RPL14 expression and EBV activity in malignant NPC cells, which is further corroborated by the suppressive effect of RPL14 on EBV infection and lytic cycle in NPC cells. Given the involvement of RPL22 45 and RPL4 46 , both of which belong to the same RPL family as RPL14 47 , in EBV infection, these findings highlight the crucial role of RPL family members in EBV life cycle. Furthermore, our study revealed that RPL14 inhibits NPC tumorigenesis, consistent with its tumor-suppressive function reported in an in vitro NPC study 48 and in other cancer types 49 .…”