Polypharmacology-based kinome screen identifies new regulators of KSHV reactivation.

Autor: Olson AT; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America., Kang Y; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America., Ladha AM; Department of Microbiology, University of Washington, Seattle, Washington, United States of America., Zhu S; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America., Lim CB; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America., Nabet B; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America., Lagunoff M; Department of Microbiology, University of Washington, Seattle, Washington, United States of America., Gujral TS; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.; Department of Pharmacology, University of Washington, Seattle, Washington, United States of America., Geballe AP; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.; Department of Microbiology, University of Washington, Seattle, Washington, United States of America.; Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.; Department of Medicine, University of Washington, Seattle, Washington, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2023 Sep 05; Vol. 19 (9), pp. e1011169. Date of Electronic Publication: 2023 Sep 05 (Print Publication: 2023).
DOI: 10.1371/journal.ppat.1011169
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Olson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje