Journal Article

Polypharmacology-based kinome screen identifies new regulators of KSHV reactivation

Kang, Yuqi, Geballe, Adam P., Olson, Annabel T., Ladha, Anushka M., Nabet, Behnam, Lagunoff, Michael, Lim, Chuan Bian, Zhu, Songli, Gujral, Taranjit S.

2023

Overview

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes several human diseases including Kaposi’s sarcoma (KS), a leading cause of cancer in Africa and in patients with AIDS. KS tumor cells harbor KSHV predominantly in a latent form, while typically <5% contain lytic replicating virus. Because both latent and lytic stages likely contribute to cancer initiation and progression, continued dissection of host regulators of this biological switch will provide insights into fundamental pathways controlling the KSHV life cycle and related disease pathogenesis. Several cellular protein kinases have been reported to promote or restrict KSHV reactivation, but our knowledge of these signaling mediators and pathways is incomplete. We employed a polypharmacology-based kinome screen to identify specific kinases that regulate KSHV reactivation. Those identified by the screen and validated by knockdown experiments included several kinases that enhance lytic reactivation: ERBB2 (HER2 or neu ), ERBB3 (HER3), ERBB4 (HER4), MKNK2 (MNK2), ITK, TEC, and DSTYK (RIPK5). Conversely, ERBB1 (EGFR1 or HER1), MKNK1 (MNK1) and FRK (PTK5) were found to promote the maintenance of latency. Mechanistic characterization of ERBB2 pro-lytic functions revealed a signaling connection between ERBB2 and the activation of CREB1, a transcription factor that drives KSHV lytic gene expression. These studies provided a proof-of-principle application of a polypharmacology-based kinome screen for the study of KSHV reactivation and enabled the discovery of both kinase inhibitors and specific kinases that regulate the KSHV latent-to-lytic replication switch.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Africa / Analysis / Artificial chromosomes / B cells / Biology and life sciences / Cancer / Care and treatment / Cells / Cellular proteins / Cognition / Cytokines / Development and progression / Disease / Drugs / ErbB-1 protein / ErbB-2 protein / ErbB-3 protein / Gene expression / Growth factors / Health aspects / Herpes viruses / Herpesvirus 8, Human - genetics / Humans / Intracellular Signaling Peptides and Proteins / Itk protein / Kaposi's sarcoma / Kinases / Latency / Medicine and Health Sciences / Pathogenesis / Patient outcomes / Peptides / Polypharmacology / Polypharmacy / Protein kinases / Protein Serine-Threonine Kinases / Receptor-Interacting Protein Serine-Threonine Kinases / Research and Analysis Methods / Sarcoma / Sarcoma, Kaposi / Signal transduction / Transcription activation / Tumor cells / Viruses