The Endoplasmic Reticulum Chaperone BiP/GRP78 is a Pro-Viral Factor that Promotes Survival and Proliferation of Cells Infected with the Oncogenic Kaposi's Sarcoma-Associated Herpesvirus
المفاهيم الأساسية
The endoplasmic reticulum (ER) chaperone BiP/GRP78 is upregulated during the lytic cycle of the oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) and acts as a pro-viral factor, promoting viral replication and the survival/proliferation of KSHV-infected cells.
الملخص
The content explores the role of the ER chaperone BiP/GRP78 during KSHV infection. Key findings:
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BiP protein levels are upregulated during the lytic phase of KSHV infection in iSLK.219 cells, independent of the unfolded protein response (UPR) that typically regulates BiP expression.
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Genetic or pharmacological inhibition of BiP disrupts KSHV lytic replication and reduces the proliferation and survival of KSHV-infected cells. This pro-viral role of BiP is not limited to KSHV but extends to other DNA viruses like herpesviruses and poxviruses.
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BiP inhibition with the small molecule HA15 has a cytostatic effect on KSHV-infected lymphoma-derived B-cells and a cytotoxic effect on KSHV-infected primary lymphatic endothelial cells, while sparing uninfected normal cells.
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The upregulation of BiP during KSHV lytic infection appears to be a post-transcriptional event, independent of the canonical UPR pathways involving XBP1 and ATF6. The mechanism by which KSHV induces BiP upregulation remains to be elucidated.
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BiP may facilitate KSHV replication by promoting the folding and maturation of viral glycoproteins required for the early stages of the lytic cycle, as evidenced by the reduced levels of the K1 viral glycoprotein upon BiP inhibition.
Overall, the findings suggest that targeting BiP could be a promising antiviral and anticancer strategy against KSHV-associated malignancies.
إعادة الكتابة بالذكاء الاصطناعي
إنشاء خريطة ذهنية
من محتوى المصدر
BiP/GRP78 is a pro-viral factor for diverse dsDNA viruses that promotes the survival and proliferation of cells upon KSHV infection
الإحصائيات
The levels of BiP protein increase significantly during the early lytic phase (24-48h) of KSHV reactivation in iSLK.219 cells.
Treatment with the BiP inhibitor HA15 reduces KSHV lytic protein expression and infectious virus production by up to 90% in iSLK.219 and TREx-BCBL-1 cells.
Silencing of BiP by siRNA in iSLK.219 cells also significantly reduces viral protein expression and infectious virion production.
HA15 treatment reduces the levels of the KSHV K1 glycoprotein, which is required for efficient lytic reactivation.
HA15 treatment at 10-30 μM concentration potently inhibits the spread of other dsDNA viruses like HSV-1, HCMV, and Vaccinia virus in primary human fibroblasts.
اقتباسات
"BiP is upregulated during the KSHV lytic cycle, independent of UPR activation."
"Genetic and pharmacological inhibition of BiP halts KSHV viral replication and reduces the proliferation and survival of KSHV-infected cells."
"Inhibition of BiP limits the spread of other alpha- and beta-herpesviruses and poxviruses with minimal toxicity for normal cells."
استفسارات أعمق
How does KSHV induce the post-transcriptional upregulation of BiP during the lytic cycle, bypassing the canonical UPR regulatory mechanisms?
During the lytic cycle of KSHV, the virus induces the upregulation of BiP post-transcriptionally, bypassing the canonical UPR regulatory mechanisms. This upregulation occurs independently of the unfolded protein response (UPR), a major signaling pathway that regulates BiP availability. In KSHV-infected cells, BiP escapes UPR regulatory control and is upregulated post-transcriptionally during the lytic infection. The virus strains present in these cells may induce an altered translational state that promotes the enhanced translation of BiP. This enhanced translation of BiP may arise from alternative initiation mechanisms, such as the use of the IRES element in the BiP mRNA or the involvement of translation initiation factors like eIF2A. These mechanisms may facilitate the translation of BiP even in conditions where cap-dependent translation is disfavored, such as during viral infections. The upregulation of BiP in KSHV-infected cells is likely driven by the need for increased protein folding and processing to support viral replication and assembly, highlighting the virus's ability to manipulate host cell machinery for its benefit.
How does KSHV induce the post-transcriptional upregulation of BiP during the lytic cycle, bypassing the canonical UPR regulatory mechanisms?
The differential sensitivity of KSHV-infected versus uninfected cells to BiP inhibition can be attributed to several specific viral and host factors. In KSHV-infected cells, the virus induces a high biosynthetic burden on the endoplasmic reticulum (ER) by synthesizing and folding numerous viral proteins, leading to an increased requirement for chaperones like BiP. The upregulation of BiP in infected cells may be a response to the increased demand for protein folding and maturation during the viral lytic cycle. Additionally, KSHV may modulate the host cell proteostasis machinery to favor the expression and function of BiP, making infected cells more dependent on BiP for viral replication. On the other hand, uninfected cells do not experience the same level of protein synthesis and folding stress as infected cells, resulting in lower basal levels of BiP and reduced sensitivity to BiP inhibition. The specific interactions between viral proteins and host factors in infected cells may also contribute to the differential sensitivity to BiP inhibition, as these interactions can alter the cellular proteostasis landscape and increase the reliance on BiP for viral replication.
Could targeting the interaction between BiP and specific KSHV glycoproteins, like K1, provide a more targeted approach to disrupt viral replication without broadly impacting cellular proteostasis?
Targeting the interaction between BiP and specific KSHV glycoproteins, such as K1, could potentially provide a more targeted approach to disrupt viral replication without broadly impacting cellular proteostasis. K1 is a KSHV glycoprotein expressed during both the latent and lytic cycles of infection and is required for efficient lytic reactivation. By specifically inhibiting the interaction between BiP and K1, it may be possible to disrupt the folding and processing of K1 without affecting the overall function of BiP in the cell. This targeted approach could potentially block the assembly and maturation of K1 and other viral proteins essential for viral replication, leading to the inhibition of viral spread without causing widespread disruption to cellular proteostasis. Further research into the specific mechanisms of interaction between BiP and KSHV glycoproteins, like K1, is needed to explore the feasibility and effectiveness of this targeted therapeutic strategy.
