Herpes simplex virus type I (HSV-1) infection leads to RNA polymerase II (RNAPII) degradation and host transcription shutdown. We show that ICP22 defines the virus-induced chaperone-enriched (VICE) domain through liquid-liquid phase separation. Condensate-disrupting point mutations of ICP22 increase ubiquitin modification of RNAPII Ser-2P; reduce its level and occupancy on viral genes; impair viral gene expression, particularly late genes; and severely reduce viral titers. When proteasome activity is blocked, ubiquitinated RNAPII Ser-2P and the viral UL36 begin to accumulate in the ICP22 condensates. The ubiquitin-specific protease (USP) deubiquitinase domain of UL36 interacts with and erases ubiquitin modification from RNAPII Ser-2P, protecting it from degradation in infected cells. A virus carrying a catalytic mutant of the UL36 USP diminishes cellular RNAPII Ser-2P levels, viral transcription, and growth. Thus, ICP22 condensates are processing centers where RNAPII Ser-2P is recruited to be deubiquitinated to ensure viral transcription when host transcription is disrupted following infection.
基金：
This study was supported by grants from the Ministry of Science and Technology of People’s Republic of China (MOST, 2023YFC
2306700 and 2018YFE0203700), the National Natural Science Foundation of
China-Yunnan Joint Found (NSFC, U2202215 and U1602226); the National
Natural Science Foundation of China (NSFC, 81672040 to J.Z., 32070169 to
W.-b.Z. and 82060175 to H.Z.), the Ministry of Science and Technology of
China Foreign Expert Program to J.Z. (G2021061008L), the CAS ‘‘Light of
West China’’ Program (xbzg-zdsys-201909) to J.Z., and the Thousand Foreign Talent scholarship from Yunnan Province and High-end Foreign Expert Project
of Yunnan Revitalization Talent Support Program to J.Z.
生物学