Leucine zipper domain is required for Kaposi sarcoma-associated herpesvirus (KSHV) K-bZIP protein to interact with histone deacetylase and is important for KSHV replication

J Biol Chem. 2012 May 4;287(19):15622-34. doi: 10.1074/jbc.M111.315861. Epub 2012 Mar 13.


The Kaposi sarcoma-associated herpesvirus (KSHV; or human herpesvirus-8)-encoded protein called K-bZIP (also named K8) was found to be multifunctional. In this study, we discovered that K-bZIP interacts with histone deacetylase (HDAC) 1/2 in 12-O-tetradecanoylphorbol-13-acetate-stimulated BCBL-1 lymphocyte cells. K-bZIP appears to repress HDAC activity through this interaction, which we determined to be independent of K-bZIP SUMOylation. We dissected the domains of K-bZIP and found that the leucine zipper (LZ) domain is essential for the interaction of K-bZIP and HDAC. In addition, we constructed a KSHV bacterial artificial chromosome (BAC) with LZ domain-deleted K-bZIP (KSHVdLZ) and transfected this mutated KSHV BAC DNA into HEK 293T cells. As a result, it was consistently found that K-bZIP without its LZ domain failed to interact with HDAC2. We also showed that the interaction between K-bZIP and HDAC is necessary for the inhibition of the lytic gene promoters (ORF50 and OriLyt) of KSHV by K-bZIP. Furthermore, we found that the LZ domain is also important for the interaction of K-bZIP with the promoters of ORF50 and OriLyt. Most interestingly, although it was found to have suppressive effects on the promoters of ORF50 and OriLyt, KSHVdLZ replicates at a significantly lower level than its BAC-derived revertant (KSHVdLZRev) or KSHVWT (BAC36) in HEK 293T cells. The defectiveness of KSHVdLZ replication can be partially rescued by siRNA against HDAC2. Our results suggest that the function of K-bZIP interaction with HDAC is two-layered. 1) K-bZIP inhibits HDAC activity generally so that KSHVdLZ replicates at a lower level than does KSHVWT. 2) K-bZIP can recruit HDAC to the promoters of OriLyt and ORF50 through interaction with HDAC for K-bZIP to have a temporary repressive effect on the two promoters.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Binding Sites / genetics
  • Blotting, Western
  • Cell Line, Tumor
  • DNA Replication
  • HEK293 Cells
  • Herpesvirus 8, Human / genetics
  • Herpesvirus 8, Human / metabolism*
  • Herpesvirus 8, Human / physiology
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism*
  • Histone Deacetylase 2 / genetics
  • Histone Deacetylase 2 / metabolism*
  • Host-Pathogen Interactions
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism
  • Leucine Zippers / genetics
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / pathology
  • Lymphoma, B-Cell / virology
  • Mutation
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • RNA Interference
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Sumoylation
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*
  • Virus Replication*


  • Basic-Leucine Zipper Transcription Factors
  • Immediate-Early Proteins
  • K8 protein, Human herpesvirus 8
  • Repressor Proteins
  • Rta protein, Human herpesvirus 8
  • Trans-Activators
  • Viral Proteins
  • Histone Deacetylase 1
  • Histone Deacetylase 2