Data_Sheet_1_Prolyl Isomerase Pin1 Regulates the Stability of Hepatitis B Virus Core Protein.PDF
The dynamic interplay between virus and host proteins is critical for establishing efficient viral replication and virus-induced pathogenesis. Phosphorylation-dependent prolyl isomerization by Pin1 provides a unique mechanism of molecular switching to control both protein function and stability. We demonstrate here that Pin1 binds and stabilizes hepatitis B virus core protein (HBc) in a phosphorylation-dependent manner, and promotes the efficient viral propagation. Phos-tag gel electrophoresis with various site-directed mutants of HBc revealed that Thr160 and Ser162 residues within the C terminal arginine-rich domain are phosphorylated concomitantly. GST pull-down assay and co-immunoprecipitation analysis demonstrated that Pin1 associated with phosphorylated HBc at the Thr160-Pro and Ser162-Pro motifs. Chemical or genetic inhibition of Pin1 significantly accelerated the rapid degradation of HBc via a lysosome-dependent pathway. Furthermore, we found that the pyruvate dehydrogenase phosphatase catalytic subunit 2 (PDP2) could dephosphorylate HBc at the Pin1-binding sites, thereby suppressing Pin1-mediated HBc stabilization. Our findings reveal an important regulatory mechanism of HBc stability catalyzed by Pin1 and may facilitate the development of new antiviral therapeutics targeting Pin1 function.
History
References
- https://doi.org//10.3389/fmicb.2017.01557
- https://doi.org//10.1093/nar/29.3.767
- https://doi.org//10.1371/journal.ppat.1002388
- https://doi.org//10.1074/jbc.m601418200
- https://doi.org//10.1016/j.cld.2019.04.007
- https://doi.org//10.1128/jvi.76.16.8124-8137.2002
- https://doi.org//10.1002/hep.29236
- https://doi.org//10.1016/j.antiviral.2017.11.015
- https://doi.org//10.1371/journal.ppat.1007488
- https://doi.org//10.1074/jbc.273.28.17680
- https://doi.org//10.1016/0092-8674(95)90405-0
- https://doi.org//10.1038/s41598-017-11015-4
- https://doi.org//10.1016/j.bbrc.2009.02.024
- https://doi.org//10.1128/JVI.01343-14
- https://doi.org//10.1128/jvi.68.12.7993-8000.1994
- https://doi.org//10.1128/jvi.72.5.3796-3803.1998
- https://doi.org//10.1074/mcp.t500024-mcp200
- https://doi.org//10.3389/fmicb.2010.00107
- https://doi.org//10.1006/viro.1999.9798
- https://doi.org//10.1128/JVI.02533-10
- https://doi.org//10.1016/j.tibs.2011.07.001
- https://doi.org//10.1038/nchembio.2007.35
- https://doi.org//10.1016/s0962-8924(02)02253-5
- https://doi.org//10.1038/nrm2261
- https://doi.org//10.1128/JVI.00394-16
- https://doi.org//10.1128/JVI.01218-12
- https://doi.org//10.1021/acschembio.5b00143
- https://doi.org//10.1038/nm.2102
- https://doi.org//10.1074/jbc.M110.114256
- https://doi.org//10.1016/j.antiviral.2018.08.014
- https://doi.org//10.18632/oncotarget.25348
- https://doi.org//10.1038/s41467-019-09867-7
- https://doi.org//10.1038/ncomms14259
- https://doi.org//10.1038/sj.gt.3301206
- https://doi.org//10.1016/j.cell.2012.02.016
- https://doi.org//10.1128/JVI.02634-12
- https://doi.org//10.1128/jvi.66.7.4107-4116.1992
- https://doi.org//10.1128/jvi.77.24.12950-12960.2003
- https://doi.org//10.1074/jbc.M110.187989
- https://doi.org//10.1053/j.gastro.2006.12.030
- https://doi.org//10.1242/jcs.00276
- https://doi.org//10.1158/1078-0432.ccr-05-0457
- https://doi.org//10.1016/s0065-3527(05)64005-5
- https://doi.org//10.1002/hep.21345
- https://doi.org//10.1007/s12072-016-9779-5
- https://doi.org//10.1038/ncb0505-435
- https://doi.org//10.1073/pnas.90.14.6459
- https://doi.org//10.3892/mmr.2018.9620
- https://doi.org//10.1016/s1097-2765(05)00083-3
CC BY 4.0