LANA

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The latency-associated nuclear antigen (LANA-1) or latent nuclear antigen (LNA, LNA-1) is a Kaposi's sarcoma-associated herpesvirus (KSHV) latent protein initially found by Moore and colleagues as a speckled nuclear antigen present in primary effusion lymphoma cells that reacts with antibodies from patients with KS. [1] It is the most immunodominant KSHV protein identified by Western-blotting as 222–234 kDa double bands migrate slower than the predicted molecular weight. [2] LANA has been suspected of playing a crucial role in modulating viral and cellular gene expression. [3] [4] [5] It is commonly used as an antigen in blood tests to detect antibodies in persons that have been exposed to KSHV. [6] [7]

KSHV or Human herpesvirus 8 (HHV-8) has been identified as the etiological agent of Kaposi’s sarcoma (KS) and certain AIDS-associated lymphomas. As KSHV establishes latent infection in tumorous foci, it invariably expresses high levels of the viral LANA protein, which is necessary and sufficient to maintain the KSHV episome.

Encoded by ORF73, LANA-1 is one of few HHV-8 encoded proteins that is highly expressed in all latently infected tumour cells; specifically, it is a phosphoprotein with an acidic internal repeat domain flanked by a carboxy-terminal domain and an amino-terminal domain. [5] LANA-1 acts as a transcriptional regulator, and it has been implicated directly in oncogenesis because of its ability to bind to the tumour-suppressing protein p53 and to the retinoblastoma protein pRb. This leads to the inactivation of p53-dependent promoters and induction of E2F-dependent genes. [8] [9]

Studies have also shown that LANA-1 can transactivate the promoter of the reverse transcriptase subunit of the human telomerase holoenzyme, [9] thus overextending a critical step in cellular transformation. [10] Paradoxically, LANA-1 has been shown to be involved in transcriptional repression [11] [12] [13] and can, moreover, interact with the mSin3/HDAC1 co-repressor complex. [12]

It has been also shown to interact with and inhibit the ATF4/CREB2 transcription factor that interacts with the basic transcription machinery [14] and to bind with two human chromosome-associated cellular proteins, MeCP2 and DEK. [12]

LANA-1 is associated with cellular chromatin and stays on the chromosomes during cell division. [15] It maintains the viral genomes during cell division by tethering the viral episomes to the chromosomes. [16] It binds directly to replication origin recognition complexes (ORCs) that are primarily associated with the terminal repeat (TR) region of the HHV-8 genome. [17]

Notes and references

  1. ↑ Moore PS, Gao SJ, Dominguez G, Cesarman E, Lungu O, Knowles DM, Garber R, Pellett PE, McGeoch DJ, Chang Y (January 1996). "Primary characterization of a herpesvirus agent associated with Kaposi's sarcoma". Journal of Virology. 70 (1): 549–58. doi:10.1128/JVI.70.1.549-558.1996. PMC   189843 . PMID   8523568.
  2. ↑ Gao SJ, Kingsley L, Hoover DR, Spira TJ, Rinaldo CR, Saah A, Phair J, Detels R, Parry P, Chang Y, Moore PS (July 1996). "Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma". The New England Journal of Medicine. 335 (4): 233–241. doi: 10.1056/NEJM199607253350403 . PMID   8657239.
  3. ↑ Kedes DH, Lagunoff M, Renne R, Ganem D (November 1997). "Identification of the gene encoding the major latency-associated nuclear antigen of the Kaposi's sarcoma-associated herpesvirus". The Journal of Clinical Investigation. 100 (10): 2606–10. doi:10.1172/JCI119804. PMC   508462 . PMID   9366576.
  4. ↑ Kellam P, Boshoff C, Whitby D, Matthews S, Weiss RA, Talbot SJ (1997). "Identification of a major latent nuclear antigen, LNA-1, in the human herpesvirus 8 genome". Journal of Human Virology. 1 (1): 19–29. PMID   10195227.
  5. 1 2 Rainbow L, Platt GM, Simpson GR, et al. (August 1997). "The 222- to 234-kilodalton latent nuclear protein (LNA) of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) is encoded by orf73 and is a component of the latency-associated nuclear antigen". Journal of Virology. 71 (8): 5915–21. doi:10.1128/JVI.71.8.5915-5921.1997. PMC   191847 . PMID   9223481.
  6. ↑ Gao SJ, Kingsley L, Li M, Zheng W, Parravicini C, Ziegler J, Newton R, Rinaldo CR, Saah A, Phair J, Detels R, Chang Y, Moore PS (August 1996). "KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma". Nature Medicine. 2 (8): 925–928. doi:10.1038/nm0896-925. PMID   8705864. S2CID   10275045.
  7. ↑ Kedes DH, Operskalski E, Busch M, Kohn R, Flood J, Ganem D (August 1996). "The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission". Nature Medicine. 2 (8): 918–924. doi:10.1038/nm0896-918. PMID   8705863. S2CID   36556102.
  8. ↑ Friborg J, Kong W, Hottiger MO, Nabel GJ (1999). "p53 inhibition by the LANA protein of KSHV protects against cell death". Nature. 402 (6764): 889–94. doi:10.1038/47266. PMID   10622254. S2CID   4345286.
  9. 1 2 Komatsu T, Ballestas ME, Barbera AJ, Kaye KM (March 2002). "The KSHV latency-associated nuclear antigen: a multifunctional protein". Frontiers in Bioscience. 7 (1–3): d726–30. doi: 10.2741/komatsu . PMID   11861213.
  10. ↑ Jeong JH, Orvis J, Kim JW, McMurtrey CP, Renne R, Dittmer DP (April 2004). "Regulation and autoregulation of the promoter for the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus". The Journal of Biological Chemistry. 279 (16): 16822–31. doi: 10.1074/jbc.M312801200 . PMID   14742422.
  11. ↑ Garber AC, Hu J, Renne R (July 2002). "Latency-associated nuclear antigen (LANA) cooperatively binds to two sites within the terminal repeat, and both sites contribute to the ability of LANA to suppress transcription and to facilitate DNA replication". The Journal of Biological Chemistry. 277 (30): 27401–11. doi: 10.1074/jbc.M203489200 . PMID   12015325.
  12. 1 2 3 Krithivas A, Young DB, Liao G, Greene D, Hayward SD (October 2000). "Human herpesvirus 8 LANA interacts with proteins of the mSin3 corepressor complex and negatively regulates Epstein-Barr virus gene expression in dually infected PEL cells". Journal of Virology. 74 (20): 9637–45. doi:10.1128/JVI.74.20.9637-9645.2000. PMC   112396 . PMID   11000236.
  13. ↑ Schwam DR, Luciano RL, Mahajan SS, Wong L, Wilson AC (September 2000). "Carboxy terminus of human herpesvirus 8 latency-associated nuclear antigen mediates dimerization, transcriptional repression, and targeting to nuclear bodies". Journal of Virology. 74 (18): 8532–40. doi:10.1128/JVI.74.18.8532-8540.2000. PMC   116365 . PMID   10954554.
  14. ↑ Lim C, Sohn H, Gwack Y, Choe J (November 2000). "Latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) binds ATF4/CREB2 and inhibits its transcriptional activation activity". The Journal of General Virology. 81 (Pt 11): 2645–52. doi: 10.1099/0022-1317-81-11-2645 . PMID   11038375.
  15. ↑ Szekely L, Chen F, Teramoto N, et al. (June 1998). "Restricted expression of Epstein-Barr virus (EBV)-encoded, growth transformation-associated antigens in an EBV- and human herpesvirus type 8-carrying body cavity lymphoma line". The Journal of General Virology. 79 (Pt 6): 1445–52. doi: 10.1099/0022-1317-79-6-1445 . PMID   9634087.
  16. ↑ Ballestas ME, Chatis PA, Kaye KM (April 1999). "Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen". Science. 284 (5414): 641–4. doi:10.1126/science.284.5414.641. PMID   10213686.
  17. ↑ Verma SC, Lan K, Choudhuri T, Robertson ES (April 2006). "Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen modulates K1 expression through its cis-acting elements within the terminal repeats". Journal of Virology. 80 (7): 3445–58. doi:10.1128/JVI.80.7.3445-3458.2006. PMC   1440413 . PMID   16537612.

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