Kaposi's sarcoma-associated herpesvirus (KSHV) oncoprotein K13 bypasses TRAFs and directly interacts with the IkappaB kinase complex to selectively activate NF-kappaB without JNK activation.
Kaposi's sarcoma herpesvirus oncoprotein vFLIP K13 is a potent activator of NF-kappaB and plays a key role in viral pathogenesis. K13 contains a putative TRAF-interacting motif, which is reportedly required for its interaction with TRAF2. The K13-TRAF2 interaction is believed to be essential for the recruitment of K13 to the I-kappaB kinase (IKK) complex and for K13-induced NF-kappaB and JNK activation. In addition, TRAF3 has been reported to be required for K13-induced NF-kappaB and JNK activation. We have re-examined the role of the TRAFs in K13 signaling and report that mutations in the putative TRAF-interacting motif of K13 have no deleterious effect on its ability to interact with the IKK complex or activation of the NF-kappaB pathway. Furthermore, endogenously expressed TRAF2 and TRAF3 do not interact with K13 and play no role in K13-induced NF-kappaB activation or its interaction with the IKK complex. Finally, K13 does not activate the JNK pathway. Our results support a model in which K13 bypasses the upstream components of the tumor necrosis factor receptor signaling pathway and directly interacts with the IKK complex to selectively activate the NF-kappaB pathway without affecting the JNK pathway. Selective NF-kappaB activation by K13 might represent a novel strategy employed by the virus to promote latency.
Matta
Hittu
H
Department of Medicine, Division of Hematology-Oncology, The University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Mazzacurati
Lucia
L
Schamus
Sandra
S
Yang
Tianbing
T
Sun
Qinmiao
Q
Chaudhary
Preet M
PM
D020816:Amino Acid Motifs; D002460:Cell Line; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D047468:Immunoprecipitation; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011487:Protein Conformation; D034622:RNA Interference; D015398:Signal Transduction; D020298:U937 Cells; D014764:Viral Proteins / Q000737:chemistry* / Q000502:physiology*
D016328:NF-kappa B; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8; D051550:I-kappa B Kinase; D048670:MAP Kinase Kinase 4