HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 53, 55570-55577, December 31, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/53/55570    most recent M408508200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Llano, M. Articles by Poeschla, E. M. Search for Related Content PubMed PubMed Citation Articles by Llano, M. Articles by Poeschla, E. M. Social Bookmarking                      What's this?

Lens Epithelium-derived Growth Factor/p75 Prevents Proteasomal Degradation of HIV-1 Integrase^*

Manuel Llano, Sharon Delgado, Maria Vanegas, and Eric M. Poeschla¶

From the Molecular Medicine Program and Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

The transcriptional coactivator lens epithelium-derived growth factor (LEDGF)/p75 acts as a chromatin tethering factor for human immunodeficiency virus type 1 (HIV-1) integrase protein, determining its nuclear localization and its tight association with nuclear DNA. Here we identify a second function for the LEDGF/p75-integrase interaction. We observed that stable introduction of HIV-1 integrase (IN) transcription units into cells made stringently LEDGF/p75-deficient by RNAi resulted in much lower steady state levels of IN protein than introduction into LEDGF/p75 wild type cells. The same LEDGF/p75-dependent disparity was observed for feline immunodeficiency virus IN. However, IN mRNA levels were equivalent in the presence and absence of LEDGF/p75. A post-translational mechanism was confirmed when the half-life of HIV-1 IN protein was found to be much shorter in LEDGF/p75-deficient cells. Proteasome inhibition fully countered this extreme instability, increasing IN protein levels to those seen in LEDGF/p75 wild type cells and implicating proteasomal destruction as the main cause of IN instability. Consistent with these data, increased ubiquitinated HIV-1 IN was found in the LEDGF/p75 knock-down cells. Moreover, restoration of LEDGF/p75 to knocked down clones rescued HIV-1 IN stability. Subcellular fractionation showed that HIV-1 IN is exclusively cytoplasmic in LEDGF/p75-deficient cells, but mainly nuclear in LEDGF/p75 wild type cells, and that cytoplasmic HIV-1 IN has a shorter half-life than nuclear HIV-1 IN. However, using LEDGF proteins defective for nuclear localization and IN interaction, we further determined that protection of HIV-1 IN from the proteasome requires neither chromatin tethering nor nuclear residence. Protection requires only interaction with LEDGF/p75, and it is independent of the subcellular localization of the IN-LEDGF complex.

Received for publication, July 27, 2004 , and in revised form, October 5, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Guggenheim 18, Mayo Clinic College of Medicine, 200 First St. S.W., Rochester, MN 55905. Tel.: 507-284-3178; Fax: 507-266-2122; E-mail: emp{at}mayo.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. Hou, D. E. Mcguinness, A. J. Prongay, B. Feld, P. Ingravallo, R. A. Ogert, C. A. Lunn, and J. A. Howe Screening for Antiviral Inhibitors of the HIV Integrase--LEDGF/p75 Interaction Using the AlphaScreenTM Luminescent Proximity Assay J Biomol Screen, June 1, 2008; 13(5): 406 - 414. [Abstract] [PDF]

				T. L. Brady, P. G. Fuerst, R. A. Dick, C. Schmidt, and D. F. Voytas Retrotransposon Target Site Selection by Imitation of a Cellular Protein Mol. Cell. Biol., February 15, 2008; 28(4): 1230 - 1239. [Abstract] [Full Text] [PDF]

				A. Mousnier, N. Kubat, A. Massias-Simon, E. Segeral, J.-C. Rain, R. Benarous, S. Emiliani, and C. Dargemont von Hippel Lindau binding protein 1-mediated degradation of integrase affects HIV-1 gene expression at a postintegration step PNAS, August 21, 2007; 104(34): 13615 - 13620. [Abstract] [Full Text] [PDF]

				G. P. Wang, A. Ciuffi, J. Leipzig, C. C. Berry, and F. D. Bushman HIV integration site selection: Analysis by massively parallel pyrosequencing reveals association with epigenetic modifications Genome Res., August 1, 2007; 17(8): 1186 - 1194. [Abstract] [Full Text] [PDF]

				M.-C. Shun, N. K. Raghavendra, N. Vandegraaff, J. E. Daigle, S. Hughes, P. Kellam, P. Cherepanov, and A. Engelman LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration Genes & Dev., July 15, 2007; 21(14): 1767 - 1778. [Abstract] [Full Text] [PDF]

				D. Derse, B. Crise, Y. Li, G. Princler, N. Lum, C. Stewart, C. F. McGrath, S. H. Hughes, D. J. Munroe, and X. Wu Human T-Cell Leukemia Virus Type 1 Integration Target Sites in the Human Genome: Comparison with Those of Other Retroviruses J. Virol., June 15, 2007; 81(12): 6731 - 6741. [Abstract] [Full Text] [PDF]

				K. K. Pandey, S. Sinha, and D. P. Grandgenett Transcriptional Coactivator LEDGF/p75 Modulates Human Immunodeficiency Virus Type 1 Integrase-Mediated Concerted Integration J. Virol., April 15, 2007; 81(8): 3969 - 3979. [Abstract] [Full Text] [PDF]

				M. Llano, D. T. Saenz, A. Meehan, P. Wongthida, M. Peretz, W. H. Walker, W. Teo, and E. M. Poeschla An Essential Role for LEDGF/p75 in HIV Integration Science, October 20, 2006; 314(5798): 461 - 464. [Abstract] [Full Text] [PDF]

				H. G. Sutherland, K. Newton, D. G. Brownstein, M. C. Holmes, C. Kress, C. A. Semple, and W. A. Bickmore Disruption of ledgf/psip1 results in perinatal mortality and homeotic skeletal transformations. Mol. Cell. Biol., October 1, 2006; 26(19): 7201 - 7210. [Abstract] [Full Text] [PDF]

				G. N. Maertens, P. Cherepanov, and A. Engelman Transcriptional co-activator p75 binds and tethers the Myc-interacting protein JPO2 to chromatin J. Cell Sci., June 15, 2006; 119(12): 2563 - 2571. [Abstract] [Full Text] [PDF]

				P. Cherepanov, A. L. B. Ambrosio, S. Rahman, T. Ellenberger, and A. Engelman From the Cover: Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75 PNAS, November 29, 2005; 102(48): 17308 - 17313. [Abstract] [Full Text] [PDF]

				M. Vanegas, M. Llano, S. Delgado, D. Thompson, M. Peretz, and E. Poeschla Identification of the LEDGF/p75 HIV-1 integrase-interaction domain and NLS reveals NLS-independent chromatin tethering J. Cell Sci., April 15, 2005; 118(8): 1733 - 1743. [Abstract] [Full Text] [PDF]