PSIP1

PC4 and SFRS1 interacting protein 1, also known as lens epithelium-derived growth factor (LEDGF/p75), dense fine speckles 70kD protein (DFS 70) or transcriptional coactivator p75/p52, is a protein that in humans is encoded by the PSIP1 gene.

PSIP1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1Z9E, 2B4J, 2M16, 2MSR, 2MTN, 2N3A, 3F9K, 3HPG, 3HPH, 3U88, 3ZEH, 4FU6
Identifiers
Aliases	PSIP1, DFS70, LEDGF, PAIP, PSIP2, p52, p75, PC4 and SFRS1 interacting protein 1
External IDs	OMIM: 603620 MGI: 2142116 HomoloGene: 13242 GeneCards: PSIP1
Gene location (Human) Chr. Chromosome 9 (human) Band 9p22.3 Start 15,464,066 bp End 15,510,995 bp
Gene location (Mouse) Chr. Chromosome 4 (mouse) Band 4|4 C3 Start 83,373,917 bp End 83,404,696 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte ganglionic eminence cerebellar hemisphere Brodmann area 9 Achilles tendon optic nerve nucleus accumbens prefrontal cortex caudate nucleus amygdala Top expressed in spermatocyte ganglionic eminence secondary oocyte abdominal wall dorsomedial hypothalamic nucleus olfactory tubercle maxillary prominence nucleus accumbens cerebellar cortex mammillary body More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding transcription coactivator activity chromatin binding protein binding supercoiled DNA binding RNA binding Cellular component cytosol nuclear periphery nucleoplasm nucleolus nucleus Biological process regulation of transcription, DNA-templated response to heat response to oxidative stress transcription, DNA-templated establishment of integrated proviral latency mRNA 5'-splice site recognition positive regulation of transcription by RNA polymerase II viral process nuclear transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 11168 101739 Ensembl ENSG00000164985 ENSMUSG00000028484 UniProt O75475 Q99JF8 RefSeq (mRNA) NM_001128217 NM_021144 NM_033222 NM_001317898 NM_001317900 NM_001290527 NM_133948 NM_001347143 NM_001355203 RefSeq (protein) NP_001121689 NP_001304827 NP_001304829 NP_066967 NP_150091 NP_001277456 NP_001334072 NP_598709 NP_001342132 Location (UCSC) Chr 9: 15.46 – 15.51 Mb Chr 4: 83.37 – 83.4 Mb PubMed search
Wikidata
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Function

PSIP1 has not been clearly linked to a specific cellular mechanism. The term LEDGF/p75 (Lens epithelium-derived growth factor) has entered common usage based on the initial characterization of PSIP1, however this is a misnomer, as the protein is present in most tissues and has no direct role in the development of lens epithelium. LEDGF/p75, a transcription coactivator, gained prominence as a host factor that assists HIV integration and is probably the only integrase interactor whose knock-down severely affects the HIV integration levels. The interaction between HIV integrase and human LEDGF/p75 is a promising target for anti-HIV drug discovery. LEDGF/p75 recruits MLL complexes to HOX genes to regulate their expression. LEDGF/p52 is shown to recruit splicing factors to H3K36 trimethylated chromatin to modulate alternative splicing, also regulates HOTTIP lncRNA, which is shown to regulate HOX genes in cis.

Structure

LEDGF/p75 is a 60kDa, 530-amino-acid-long protein. The N-terminal portion of the protein consists of a PWWP domain, a nuclear localization sequence, and two copies of the AT-hook DNA binding motif. The C-terminal portion of LEDGF/p75 contains a structure termed the integrase-binding domain, which interacts with lentiviral integrase proteins as well as numerous cellular proteins. The N-terminal portion interacts strongly with chromatin, making LEDGF/p75 a constitutively nuclear protein. An isoform of the protein, LEDGF/p52, is produced by alternative splicing. LEDGF/p52 shares the N-terminal 325 amino acids of LEDGF/p75 but lacks the integrase-binding domain.

Interactions

PSIP1 has been shown to interact with the proteins ASF/SF2, JPO2, Cdc7-Dbf4, and POGZ as well as the menin/MLL protein complex.

Further reading

• Shun MC, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, Cherepanov P, Engelman A (July 2007). "LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration". Genes Dev. 21 (14): 1767–78. doi:10.1101/gad.1565107. PMC 1920171. PMID 17639082.
• Van Maele B, Debyser Z (2005). "HIV-1 integration: an interplay between HIV-1 integrase, cellular and viral proteins". AIDS Rev. 7 (1): 26–43. PMID 15875659.
• Van Maele B, Busschots K, Vandekerckhove L, Christ F, Debyser Z (2006). "Cellular co-factors of HIV-1 integration". Trends Biochem. Sci. 31 (2): 98–105. doi:10.1016/j.tibs.2005.12.002. PMID 16403635.
• Freed EO, Mouland AJ (2006). "The cell biology of HIV-1 and other retroviruses". Retrovirology. 3: 77. doi:10.1186/1742-4690-3-77. PMC 1635732. PMID 17083721.
• Ge H, Si Y, Roeder RG (1998). "Isolation of cDNAs encoding novel transcription coactivators p52 and p75 reveals an alternate regulatory mechanism of transcriptional activation". EMBO J. 17 (22): 6723–9. doi:10.1093/emboj/17.22.6723. PMC 1171017. PMID 9822615.
• Ge H, Si Y, Wolffe AP (1998). "A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2". Mol. Cell. 2 (6): 751–9. doi:10.1016/S1097-2765(00)80290-7. PMID 9885563.
• Singh DP, Ohguro N, Kikuchi T, Sueno T, Reddy VN, Yuge K, Chylack LT, Shinohara T (2000). "Lens epithelium-derived growth factor: effects on growth and survival of lens epithelial cells, keratinocytes, and fibroblasts". Biochem. Biophys. Res. Commun. 267 (1): 373–81. doi:10.1006/bbrc.1999.1979. PMID 10623627.
• Singh DP, Kimura A, Chylack LT, Shinohara T (2000). "Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing". Gene. 242 (1–2): 265–73. doi:10.1016/S0378-1119(99)00506-5. PMID 10721720.
• Ochs RL, Muro Y, Si Y, Ge H, Chan EK, Tan EM (2000). "Autoantibodies to DFS 70 kd/transcription coactivator p75 in atopic dermatitis and other conditions". J. Allergy Clin. Immunol. 105 (6 Pt 1): 1211–20. doi:10.1067/mai.2000.107039. PMID 10856157.
• Kubo E, Fatma N, Sharma P, Shinohara T, Chylack LT, Akagi Y, Singh DP (2002). "Transactivation of involucrin, a marker of differentiation in keratinocytes, by lens epithelium-derived growth factor (LEDGF)". J. Mol. Biol. 320 (5): 1053–63. doi:10.1016/S0022-2836(02)00551-X. PMID 12126624.
• Wu X, Daniels T, Molinaro C, Lilly MB, Casiano CA (2002). "Caspase cleavage of the nuclear autoantigen LEDGF/p75 abrogates its pro-survival function: implications for autoimmunity in atopic disorders". Cell Death Differ. 9 (9): 915–25. doi:10.1038/sj.cdd.4401063. PMID 12181742.
• Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, De Clercq E, Debyser Z (2003). "HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells". J. Biol. Chem. 278 (1): 372–81. doi:10.1074/jbc.M209278200. PMID 12407101.
• Maertens G, Cherepanov P, Pluymers W, Busschots K, De Clercq E, Debyser Z, Engelborghs Y (2003). "LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells". J. Biol. Chem. 278 (35): 33528–39. doi:10.1074/jbc.M303594200. PMID 12796494.
• Maertens G, Cherepanov P, Debyser Z, Engelborghs Y, Engelman A (2004). "Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75". J. Biol. Chem. 279 (32): 33421–9. doi:10.1074/jbc.M404700200. PMID 15163664.
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proc. Natl. Acad. Sci. U.S.A. 101 (33): 12130–5. Bibcode:2004PNAS..10112130B. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.
• Llano M, Vanegas M, Fregoso O, Saenz D, Chung S, Peretz M, Poeschla EM (2004). "LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes". J. Virol. 78 (17): 9524–37. doi:10.1128/JVI.78.17.9524-9537.2004. PMC 506940. PMID 15308744.
• Cherepanov P, Devroe E, Silver PA, Engelman A (2004). "Identification of an evolutionarily conserved domain in human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1 integrase". J. Biol. Chem. 279 (47): 48883–92. doi:10.1074/jbc.M406307200. PMID 15371438.
• Llano M, Delgado S, Vanegas M, Poeschla EM (2004). "Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase". J. Biol. Chem. 279 (53): 55570–7. doi:10.1074/jbc.M408508200. PMID 15475359.
• Ogawa Y, Sugiura K, Watanabe A, Kunimatsu M, Mishima M, Tomita Y, Muro Y (2004). "Autoantigenicity of DFS70 is restricted to the conformational epitope of C-terminal alpha-helical domain". J. Autoimmun. 23 (3): 221–31. doi:10.1016/j.jaut.2004.07.003. PMID 15501393.
• Okamoto M, Ogawa Y, Watanabe A, Sugiura K, Shimomura Y, Aoki N, Nagasaka T, Tomita Y, Muro Y (2004). "Autoantibodies to DFS70/LEDGF are increased in alopecia areata patients". J. Autoimmun. 23 (3): 257–66. doi:10.1016/j.jaut.2004.07.004. PMID 15501396.