Human herpesvirus–encoded kinase induces B cell lymphomas in vivo

Anders, Penny; Montgomery, Nathan D.; Montgomery, Stephanie A.; Bhatt, Aadra P.; Dittmer, Dirk P.; Damania, Blossom

doi:10.1172/jci97053

Cited by 25 publications

(19 citation statements)

References 83 publications

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“…vPK appears to resemble cellular ribosomal protein S6 kinase (S6KB1; a kinase downstream of AKT–mTOR complex 1 (mTORC1) signalling) and to phosphorylate ribosomal protein S6 in vitro to increase protein synthesis and augment anchorage-independent growth, angiogenesis and cell proliferation 91 . In addition, KSHV vPK transgenic mice develop lymphomas 105 . Another protein, KSHV ORF45, binds to cellular ribosomal S6 kinase 1 (RSK1) and RSK2, stabilizing its interaction with ERK and preventing its dephosphorylation, which is important for lytic replication 90 .…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Kaposi sarcoma

Cesarman

Damania

Krown³

et al. 2019

Nat Rev Dis Primers

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407

448

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Kaposi sarcoma (KS) gained public attention as an AIDS-defining malignancy; its appearance on the skin was a highly stigmatizing sign of HIV infection during the height of the AIDS epidemic. The widespread introduction of effective antiretrovirals to control HIV by restoring immunocompetence reduced the prevalence of AIDS-related KS, although KS does occur in individuals with well-controlled HIV infection. KS also presents in individuals without HIV infection in older men (classic KS), in sub-Saharan Africa (endemic KS) and in transplant recipients (iatrogenic KS). The aetiologic agent of KS is KS herpesvirus (KSHV; also known as human herpesvirus-8), and viral proteins can induce KS-associated cellular changes that enable the virus to evade the host immune system and allow the infected cell to survive and proliferate despite viral infection. Currently, most cases of KS occur in sub-Saharan Africa, where KSHV infection is prevalent owing to transmission by saliva in childhood compounded by the ongoing AIDS epidemic. Treatment for early AIDS-related KS in previously untreated patients should start with the control of HIV with antiretrovirals, which frequently results in KS regression. In advanced-stage KS, chemotherapy with pegylated liposomal doxorubicin or paclitaxel is the most common treatment, although it is seldom curative. In sub-Saharan Africa, KS continues to have a poor prognosis. Newer treatments for KS based on the mechanisms of its pathogenesis are being explored.

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Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Kaposi sarcoma

Cesarman

Damania

Krown³

et al. 2019

Nat Rev Dis Primers

Self Cite

407

448

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“…Indeed, prolonged expression of the ORF36 homolog in EBV (BGLF4) can contribute to genome instability leading to tumor formation, which has been linked to its phosphorylation of lamin A/C and topoisomerase-II [72, 73]. KSHV ORF36 also displays functions associated with oncogenesis, including functional mimicry of the cellular ribosomal protein S6 kinase β-1 (S6KB1), which leads to enhanced protein synthesis, endothelial capillary tubule formation and anchorage-independent growth [74]. Notably, a recent study from the Damania lab showed that transgenic mice expressing KSHV ORF36 display increased B cell activation and develop high-grade B cell lymphomas that share many features of primary effusion lymphoma [75].…”

Section: Discussionmentioning

confidence: 99%

The conserved herpesviral kinase ORF36 activates B2 retrotransposons during murine gammaherpesvirus infection

Schaller

Tucker

Willis

et al. 2020

Preprint

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ABSTRACTShort interspersed nuclear elements (SINEs) are RNA polymerase III (RNAPIII) transcribed, retrotransposable noncoding RNA (ncRNA) elements ubiquitously spread throughout mammalian genomes. While normally silenced in healthy somatic tissue, SINEs can be induced during infection with DNA viruses, including the model murine gammaherpesvirus MHV68. Here, we explored the mechanisms underlying MHV68 activation of SINE ncRNAs. We demonstrate that lytic MHV68 infection of B cells, macrophages and fibroblasts leads to robust activation of the B2 family of SINEs in a cell autonomous manner. B2 ncRNA induction requires neither host innate immune signaling factors nor involvement of the RNAPIII master regulator Maf1. However, we identify MHV68 ORF36, the conserved herpesviral kinase, as playing a key role in B2 induction during lytic infection. SINE activation is linked to ORF36 kinase activity and can also be induced by HDAC1/2 inhibition, which is one of the known ORF36 functions. Collectively, our data suggest that ORF36-mediated changes in chromatin modification contribute to B2 activation during MHV68 infection, and that this activity is conserved in other herpesviral protein kinase homologs.AUTHOR SUMMARYViral infection dramatically changes the levels of many types of RNA in a cell. In particular, certain oncogenic viruses activate expression of repetitive genes called retrotransposons, which are normally silenced due to their ability to copy and spread throughout the genome. Here, we established that infection with the gammaherpesvirus MHV68 leads to a dramatic induction of a class of noncoding retrotransposons called B2 SINEs in multiple cell types. We then explored how MHV68 activates B2 SINEs, revealing a role for the conserved herpesviral protein kinase ORF36. Both ORF36 kinase-dependent and kinase-independent functions contribute to B2 induction, perhaps through ORF36 targeting of proteins involved in controlling the accessibility of chromatin surrounding SINE loci. Understanding features underlying induction of these elements following MHV68 infection should provide insight into core elements of SINE regulation, as well as dis-regulation of SINE elements associated with disease.

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“…Considering our discovery that the conserved gammaherpesvirus protein kinase facilitates germinal center responses during early infection, it is tempting to speculate that the gammaherpesvirus protein kinase may also contribute to viral lymphomagenesis. Indeed, an elegant study by (37). Importantly, KSHV protein kinase transgenic mice displayed elevated numbers of germinal center B cells and developed viral protein kinase-positive B cell lymphomas that were of germinal center or postgerminal center origin.…”

Section: Discussionmentioning

confidence: 99%

Conserved Gammaherpesvirus Protein Kinase Selectively Promotes Irrelevant B Cell Responses

Darrah

Jondle

Johnson

et al. 2019

J Virol

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Gammaherpesviruses are ubiquitous pathogens that are associated with B cell lymphomas. In the early stages of chronic infection, these viruses infect naive B cells and subsequently usurp the B cell differentiation process through the germinal center response to ensure latent infection of long-lived memory B cells. A unique feature of early gammaherpesvirus chronic infection is a robust differentiation of irrelevant, virus-nonspecific B cells with reactivities against self-antigens and antigens of other species. In contrast, protective, virus-specific humoral responses do not reach peak levels until a much later time. While several host factors are known to either promote or selectively restrict gammaherpesvirus-driven germinal center response, viral mechanisms that contribute to the irrelevant B cell response have not been defined. In this report we show that the expression and the enzymatic activity of the gammaherpesvirus-encoded conserved protein kinase selectively facilitates the irrelevant, but not virus-specific, B cell responses. Further, we show that lack of interleukin-1 (IL-1) receptor attenuates gammaherpesvirus-driven B cell differentiation and viral reactivation. Because germinal center B cells are thought to be the target of malignant transformation during gammaherpesvirus-driven lymphomagenesis, identification of host and viral factors that promote germinal center responses during gammaherpesvirus infection may offer an insight into the mechanism of gammaherpesvirus pathogenesis. IMPORTANCE Gammaherpesviruses are ubiquitous cancer-associated pathogens that usurp the B cell differentiation process to establish life-long latent infection in memory B cells. A unique feature of early gammaherpesvirus infection is the robust increase in differentiation of B cells that are not specific for viral antigens and instead encode antibodies that react with self-antigens and antigens of other species. Viral mechanisms that are involved in driving such irrelevant B cell differentiation are not known. Here, we show that gammaherpesvirus-encoded conserved protein kinase and host IL-1 signaling promote irrelevant B cell responses and gammaherpesvirusdriven germinal center responses, with the latter thought to be the target of viral transformation.

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Human herpesvirus–encoded kinase induces B cell lymphomas in vivo

Cited by 25 publications

References 83 publications

Kaposi sarcoma

Kaposi sarcoma

The conserved herpesviral kinase ORF36 activates B2 retrotransposons during murine gammaherpesvirus infection

Conserved Gammaherpesvirus Protein Kinase Selectively Promotes Irrelevant B Cell Responses

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