The inflammatory kinase MAP4K4 promotes reactivation of Kaposi's sarcoma herpesvirus and enhances the invasiveness of infected endothelial cells.
Kaposi's sarcoma (KS) is a mesenchymal tumour, which is caused by Kaposi's sarcoma herpesvirus (KSHV) and develops under inflammatory conditions. KSHV-infected endothelial spindle cells, the neoplastic cells in KS, show increased invasiveness, attributed to the elevated expression of metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). The majority of these spindle cells harbour latent KSHV genomes, while a minority undergoes lytic reactivation with subsequent production of new virions and viral or cellular chemo- and cytokines, which may promote tumour invasion and dissemination. In order to better understand KSHV pathogenesis, we investigated cellular mechanisms underlying the lytic reactivation of KSHV. Using a combination of small molecule library screening and siRNA silencing we found a STE20 kinase family member, MAP4K4, to be involved in KSHV reactivation from latency and to contribute to the invasive phenotype of KSHV-infected endothelial cells by regulating COX-2, MMP-7, and MMP-13 expression. This kinase is also highly expressed in KS spindle cells in vivo. These findings suggest that MAP4K4, a known mediator of inflammation, is involved in KS aetiology by regulating KSHV lytic reactivation, expression of MMPs and COX-2, and, thereby modulating invasiveness of KSHV-infected endothelial cells.
Institute of Virology, Hannover Medical School, Hannover, Germany.
Darya A
DA
Haas
Kiran
K
Bala
Guntram
G
Büsche
Magdalena
M
Weidner-Glunde
Susann
S
Santag
Semra
S
Kati
Silvia
S
Gramolelli
Modester
M
Damas
Oliver
O
Dittrich-Breiholz
Michael
M
Kracht
Jessica
J
Rückert
Zoltan
Z
Varga
György
G
Keri
Thomas F
TF
Schulz
D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis / Q000235:genetics; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014775:Virus Activation / Q000502:physiology*
D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C117090:MAP4K4 protein, human; D017346:Protein Serine-Threonine Kinases; D053509:Matrix Metalloproteinase 13; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7