Bortezomib promotes KHSV and EBV lytic cycle by activating JNK and autophagy

Granato, Marisa; Romeo, Maria Anele; Tiano, Mariangela Sara; Santarelli, Roberta; Gonnella, Roberta; Montani, Maria Saveria Gilardini; Faggioni, Alberto; Cirone, Mara

doi:10.1038/s41598-017-13533-7

Cited by 42 publications

(37 citation statements)

References 37 publications

(51 reference statements)

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“…In addition, we found that the final phases of autophagy were inhibited by EBV, allowing the virus to avoid its own elimination by the lysosomal proteases and to usurp the autophagic machinery for intracellular transportation [ 6 ]. Later on, we have demonstrated that, depending on the lytic cycle inducing treatment, a PKC theta–p38MAPK axis [ 41 ] or JNK1/2 [ 42 ] play a major role in promoting viral replication through the induction of autophagy. Other studies have investigated this aspect of EBV biology, demonstrating that the virus recruits Atg8–LC3 coupled membranes to its envelope in the cytosol, and uses autophagic membranes for efficient envelope acquisition during lytic infection [ 43 ].…”

Section: Ebv Lytic Reactivation and Autophagymentioning

confidence: 99%

EBV and KSHV Infection Dysregulates Autophagy to Optimize Viral Replication, Prevent Immune Recognition and Promote Tumorigenesis

Cirone

2018

Viruses

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Autophagy is a catabolic process strongly involved in the immune response, and its dysregulation contributes to the onset of several diseases including cancer. The human oncogenic gammaherpesviruses, Epstein—Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), manipulate autophagy, either during the de novo infection or during the lytic reactivation, in naturally latently-infected lymphoma cells. In particular, the gammaherpesvirus infection reduces autophagy in immune cells, such as monocytes, resulting in the impairment of cell survival and cell differentiation into dendritic cells (DCs), which are essential for initiating and regulating the immune response. In the case of EBV, the reduction of autophagy in these cells, leading to p62 accumulation, activated the p62-NRF2-antioxidant response, reducing ROS, and further inhibiting autophagy. KSHV inhibits autophagy in monocytes by de-phosphorylating JNK2, altering the calpains–calpastatin balance and increasing the calpain activity responsible for the cleavage of ATG5. To further impair the immune response, KSHV also inhibits autophagy in differentiated DCs by hyper-phosphorylating STAT3. Conversely, when the lytic cycle is induced in vitro in latently-infected lymphoma B cells, both EBV and KSHV promote autophagy to enhance their replication, although the final autophagic steps are blocked through the down-regulation of Rab7. This strategy allows viruses to avoid the destructive environment of lysosomes, and to exploit the autophagic machinery for intracellular transportation. EBV and KSHV encode for proteins that may either inhibit or promote autophagy and, in addition, they can modulate the cellular pathways that control this process. In this review we will discuss the findings that indicate that autophagy is dysregulated by gammaherpesvirus to promote immune suppression, facilitate viral replication and contribute to the onset and maintenance of gammaherpesvirus-associated malignancies.

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Section: Ebv Lytic Reactivation and Autophagymentioning

confidence: 99%

EBV and KSHV Infection Dysregulates Autophagy to Optimize Viral Replication, Prevent Immune Recognition and Promote Tumorigenesis

Cirone

2018

Viruses

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“…For HSV-1, IRE1 activation could activate JNK, which has been shown to support viral replication in multiple cell types [101]. JNK has also been shown to play important roles in KSHV infection; de novo infection triggers JNK activation, and ER stress-induced JNK activation can reactivate KSHV from latency [110,111]. Later stages of KSHV lytic replication also feature JNK activation, and ectopic expression experiments have shown that KSHV lytic proteins K15 and vGPCR can induce JNK phosphorylation [112,113].…”

Section: Discussionmentioning

confidence: 99%

KSHV activates unfolded protein response sensors but suppresses downstream transcriptional responses to support lytic replication

Johnston

McCormick

2018

Preprint

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Herpesviruses usurp host cell protein synthesis machinery to convert viral mRNAs into proteins, and the endoplasmic reticulum (ER) to ensure proper folding, post-translational modification and trafficking of secreted viral proteins. Overloading ER folding capacity activates the unfolded protein response (UPR), whereby displacement of the ER chaperone BiP activates UPR sensor proteins ATF6, PERK and IRE1 to initiate transcriptional responses to increase catabolic processes and ER folding capacity, while suppressing bulk protein synthesis. Kaposi’s sarcoma-associated herpesvirus (KSHV) can be reactivated from latency by chemical induction of ER stress, whereby the IRE1 endoribonuclease cleaves XBP1 mRNA, resulting in a ribosomal frameshift that yields the XBP1s transcription factor that transactivates the promoter of K-RTA, the viral lytic switch protein. By incorporating XBP1s responsive elements in the K-RTA promoter KSHV appears to have evolved a mechanism to respond to ER stress. Here, we report that following reactivation from latency, KSHV lytic replication causes activation of ATF6, PERK and IRE1 UPR sensor proteins. UPR sensor activation is required for efficient KSHV lytic replication; genetic or pharmacologic inhibition of each UPR sensor diminishes virion production. Despite strong UPR sensor activation during KSHV lytic replication, downstream UPR transcriptional responses were restricted; 1) ATF6 was cleaved to release the ATF6(N) transcription factor but known ATF6(N)-responsive genes were not transcribed; 2) PERK phosphorylated eIF2α but ATF4 did not accumulate as expected; 3) IRE1 caused XBP1 mRNA splicing, but XBP1s protein failed to accumulate and XBP1s-responsive genes were not transcribed. Remarkably, complementation of XBP1s deficiency during KSHV lytic replication by ectopic expression inhibited the production of infectious virions in a dose-dependent manner. Therefore, while XBP1s plays an important role in reactivation from latency, it inhibits later steps in lytic replication, which the virus overcomes by preventing its synthesis. Taken together, these findings suggest that KSHV hijacks UPR sensors to promote efficient viral replication while sustaining ER stress.Author summaryHuman herpesvirus-8 is the most recently discovered human herpesvirus, and it is the infectious cause of Kaposi’s sarcoma, which is why it’s also known as Kaposi’s sarcoma-associated herpesvirus (KSHV). Like all herpesviruses, KSHV replicates in the cell nucleus and uses host cell machinery to convert viral genes into proteins. Some of these proteins are synthesized, folded and modified in the endoplasmic reticulum (ER) and traverse the cellular secretory apparatus. Because the virus heavily utilizes the ER to make and process proteins, there is potential to overwhelm the system, which could impede viral replication and in extreme cases, kill the cell. Normally, when demands on the protein folding machinery are exceeded then misfolded proteins accumulate and activate the unfolded protein response (UPR). The UPR resolves ER stress by putting the brakes on synthesis of many proteins, while signaling to the nucleus to turn on a program that aims to correct this imbalance. Previous work has shown that KSHV is ‘wired’ to sense ER stress, which it uses to reactivate from a largely inactive state known as latency, in order to make more viruses. Specifically, a UPR sensor protein called IRE1 senses the accumulation of unfolded proteins in the ER and rededicates a gene called XBP1 to the production of a transcription factor called XBP1s through an unconventional cytoplasmic mRNA splicing event. XBP1s travels to the cell nucleus and stimulates the production of a collection of proteins that mitigate ER stress. In latently infected cells, XBP1s also binds to the KSHV genome and causes the production of K-RTA, a viral transcription factor that initiates the switch from latency to productive lytic replication. This achieves stress-induced initiation of KSHV replication, but nothing is known about how ER stress and the UPR affect progress through the KSHV replication cycle. Here we show that as KSHV replication progresses, all three known UPR sensor proteins, IRE1, ATF6 and PERK, are activated, which is required for efficient viral replication. Normally, activation of each of these three sensor proteins communicates a unique signal to the cell nucleus to stimulate the production of ER stress mitigating proteins, but in KSHV lytic replication all downstream communication is stymied. The failure to resolve ER stress would normally be expected to put the virus at a disadvantage, but we demonstrate that reversal of this scenario is worse; when we add extra XBP1s to the system to artificially stimulate the production of UPR responsive genes, virus replication is blocked at a late stage and no progeny viruses are released from infected cells. Taken together, these observations suggest that KSHV requires UPR sensor protein activation to replicate but has dramatically altered the outcome to prevent the synthesis of new UPR proteins and sustain stress in the ER compartment.

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“…Recent pathological and molecular findings have led researchers to examine the therapeutic potential of several molecular targeting agents, including proteasome inhibitors, immunomodulatory agents, and PI3K inhibitors [120][121][122][123]. Most results are based on in vitro data, and further evaluation (in prospective clinical trials if possible) is necessary before such agents can be used as a treatment for patients with PTLD.…”

Section: Possible Future Therapymentioning

confidence: 99%

Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disorders after Hematopoietic Stem Cell Transplantation: Pathogenesis, Risk Factors and Clinical Outcomes

Fujimoto

Suzuki

2020

Cancers

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Epstein-Barr virus (EBV) is a ubiquitous virus belonging to the human γ-herpes virus subfamily. After primary infection, EBV maintains a life-long latent infection. A major concern is that EBV can cause a diverse range of neoplasms and autoimmune diseases. In addition, patients undergoing hematopoietic stem cell transplantation or solid organ transplantation can experience post-transplant lymphoproliferative disorders (PTLDs) due to dysfunction or suppression of host’s immune system, or uncontrolled proliferation of EBV-infected cells. In recent years, the number of EBV-associated PTLD cases has increased. This review focuses on the current understandings of EBV-associated PTLD pathogenesis, as well as the risk factors and clinical outcomes for patients after allogeneic stem cell transplantation.

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Bortezomib promotes KHSV and EBV lytic cycle by activating JNK and autophagy

Cited by 42 publications

References 37 publications

EBV and KSHV Infection Dysregulates Autophagy to Optimize Viral Replication, Prevent Immune Recognition and Promote Tumorigenesis

EBV and KSHV Infection Dysregulates Autophagy to Optimize Viral Replication, Prevent Immune Recognition and Promote Tumorigenesis

KSHV activates unfolded protein response sensors but suppresses downstream transcriptional responses to support lytic replication

Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disorders after Hematopoietic Stem Cell Transplantation: Pathogenesis, Risk Factors and Clinical Outcomes

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