title: SLX4-SLX1 Protein-independent Down-regulation of MUS81-EME1 Protein by HIV-1 Viral Protein R (Vpr).
abstract: Evolutionarily conserved structure-selective endonuclease MUS81 forms a complex with EME1 and further associates with another endonuclease SLX4-SLX1 to form a four-subunit complex of MUS81-EME1-SLX4-SLX1, coordinating distinctive biochemical activities of both endonucleases in DNA repair. Viral protein R (Vpr), a highly conserved accessory protein in primate lentiviruses, was previously reported to bind SLX4 to mediate down-regulation of MUS81. However, the detailed mechanism underlying MUS81 down-regulation is unclear. Here, we report that HIV-1 Vpr down-regulates both MUS81 and its cofactor EME1 by hijacking the host CRL4-DCAF1 E3 ubiquitin ligase. Multiple Vpr variants, from HIV-1 and SIV, down-regulate both MUS81 and EME1. Furthermore, a C-terminally truncated Vpr mutant and point mutants R80A and Q65R, all of which lack G2 arrest activity, are able to down-regulate MUS81-EME1, suggesting that Vpr-induced G2 arrest is not correlated with MUS81-EME1 down-regulation. We also show that neither the interaction of MUS81-EME1 with Vpr nor their down-regulation is dependent on SLX4-SLX1. Together, these data provide new insight on a conserved function of Vpr in a host endonuclease down-regulation.
authors.affiliation: From the Department of Structural Biology and Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: From the Department of Structural Biology and Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
authors.forename: Maria
authors.initials: M
authors.lastname: DeLucia
authors.affiliation: From the Department of Structural Biology and Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260 jia12@pitt.edu.
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Ahn
mesh_terms: D019943:Amino Acid Substitution; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation; D004706:Endodeoxyribonucleases / Q000096:biosynthesis* / Q000235:genetics; D004720:Endonucleases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases; D045522:Recombinases / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D053722:Receptors, Interleukin-17
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D017346:Protein Serine-Threonine Kinases; D045522:Recombinases; D044767:Ubiquitin-Protein Ligases; D054325:vpr Gene Products, Human Immunodeficiency Virus; C408922:IL17RB protein, human; D053722:Receptors, Interleukin-17; C514912:vpr protein, Human immunodeficiency virus 1; C530533:DCAF1 protein, human; C507947:Eme1 protein, human; C498772:MUS81 protein, human; C542320:SLX1 protein, human; C542319:SLX4 protein, human
keywords: E3 ubiquitin ligase; Western blot; human immunodeficiency virus (HIV); proteasome; protein degradation; viral protein