Oliver I Fregoso
Assistant Professor, MIMG, University of California Los Angeles
HIV-1 is one of the most devastating viral pathogens in modern human history. Despite fervent research, it still presents a major burden to human health, particularly in underserved populations. HIV belongs to a family of viruses called lentiviruses that infect at least 40 primate species. The success of this family is due to its ability to adapt to the host environment and circumvent the innate immune responses. This is largely achieved through co-option of host proteins to function as pro-viral cofactors, as well as through direct antagonism of host anti-viral proteins. Our research focuses on elucidating viral-host interactions that regulate lentiviral replication and pathogenesis. Our goal is to identify important proteins involved in the lentiviral lifecycle, as well as to uncover the molecular constraints governing viral evolution and adaptation. We take a unique interdisciplinary approach to study these interactions by combining molecular virology, biochemistry, and evolutionary biology. By studying host genes from a diverse array of primates, as well as the viruses that specifically infect these primates, we are able to identify viral-host interactions that are necessary for lentiviral pathogenesis and adaptation to a new host.
A current focus of the lab is on understanding the role of the DNA damage response in the lentiviral lifecycle. Through our unbiased evolutionary approach, we have identified proteins canonically involved in the cells response to damaged DNA as important lentiviral factors. The overall goal of these studies is (a) to gain a mechanistic understanding of how viral accessory proteins modulate the DNA damage response, and (b) to describe uncharacterized host factors that regulate the lentiviral lifecycle. This is a largely unexplored interface of lentiviral and host biology. Understanding how and why lentiviruses engage the DNA damage response will shed light on both viral and host biology, and further help to expand our fight against HIV.
Dr. Fregoso received his bachelors degrees at UC Santa Cruz in both Molecular, Cellular, and Developmental Biology and Studio Art. He received his PhD from The Watson School of Biological Sciences at Cold Spring Harbor Laboratory. He studied with Dr. Adrian Krainer and Dr. Michael Myers, where he used proteomic techniques to understand how the interactomes of highly related splicing-regulatory proteins ultimately lead to their distinct cellular functions. His work contributed to the understanding of how protein-protein and protein-RNA interactions differentially regulate alternative splicing activators and repressors, and how these interactions contribute to the role of splicing factors in oncogenesis.
Dr. Fregoso pursued his postdoctoral research with Dr. Michael Emerman at the Fred Hutchinson Cancer Research Center. His research focused on the lentiviral accessory genes Vpr and Vpx, and the host proteins they interact with. Through the use of molecular, biochemical, and evolutionary techniques, his work identified the evolutionary arms race engaged by these viral and host proteins. In elucidating this arms race, he identified a novel means by which Vpr and Vpx counteract host antiviral proteins, and further characterized the specific pressures that drove the evolution of these viral factors.
Dr. Fregoso joined the MIMG faculty in spring of 2016.
- Johnson JR, Crosby DC, Hultquist JF, Kurland AP, Adhikary P, Li D, Marlett J, Swann J, Hüttenhain R, Verschueren E, Johnson TL, Newton BW, Shales M, Simon VA, Beltrao P, Frankel AD, Marson A, Cox JS, Fregoso OI, Young JAT, Krogan NJ. Global post-translational modification profiling of HIV-1-infected cells reveals mechanisms of host cellular pathway remodeling.. Cell reports, 2022.
- Lopez A, Nichols Doyle R, Sandoval C, Nisson K, Yang V, Fregoso OI. Viral Modulation of the DNA Damage Response and Innate Immunity: Two Sides of the Same Coin.. Journal of molecular biology, 2021.
- Li D, Lopez A, Sandoval C, Nichols Doyle R, Fregoso OI. HIV Vpr Modulates the Host DNA Damage Response at Two Independent Steps to Damage DNA and Repress Double-Strand DNA Break Repair.. mBio, 2020.
- Aznarez I, Nomakuchi TT, Tetenbaum-Novatt J, Rahman MA, Fregoso O, Rees H, Krainer AR. Mechanism of Nonsense-Mediated mRNA Decay Stimulation by Splicing Factor SRSF1.. Cell reports, 2018.
- Fregoso OI. Mind Your Cs and Gs.. Cell host & microbe, 2017.
- Baldauf HM, Stegmann L, Schwarz SM, Ambiel I, Trotard M, Martin M, Burggraf M, Lenzi GM, Lejk H, Pan X, Fregoso OI, Lim ES, Abraham L, Nguyen LA, Rutsch F, König R, Kim B, Emerman M, Fackler OT, Keppler OT. Vpx overcomes a SAMHD1-independent block to HIV reverse transcription that is specific to resting CD4 T cells.. Proceedings of the National Academy of Sciences of the United States of America, 2017.
- Fregoso OI, Emerman M. Activation of the DNA Damage Response Is a Conserved Function of HIV-1 and HIV-2 Vpr That Is Independent of SLX4 Recruitment.. mBio, 2016.
- Akerman M, Fregoso OI, Das S, Ruse C, Jensen MA, Pappin DJ, Zhang MQ, Krainer AR. Differential connectivity of splicing activators and repressors to the human spliceosome.. Genome biology, 2015.
- Fregoso OI, Ahn J, Wang C, Mehrens J, Skowronski J, Emerman M. Evolutionary toggling of Vpx/Vpr specificity results in divergent recognition of the restriction factor SAMHD1.. PLoS pathogens, 2013.
- Das S, Fregoso OI, Krainer AR. A new path to oncogene-induced senescence: at the crossroads of splicing and translation.. Cell cycle (Georgetown, Tex.), 2013.
- Fregoso OI, Das S, Akerman M, Krainer AR. Splicing-factor oncoprotein SRSF1 stabilizes p53 via RPL5 and induces cellular senescence.. Molecular cell, 2013.
- Bueno MT, Reyes D, Valdes L, Saheba A, Urias E, Mendoza C, Fregoso OI, Llano M. Poly(ADP-ribose) polymerase 1 promotes transcriptional repression of integrated retroviruses.. Journal of virology, 2012.
- Lim ES, Fregoso OI, McCoy CO, Matsen FA, Malik HS, Emerman M. The ability of primate lentiviruses to degrade the monocyte restriction factor SAMHD1 preceded the birth of the viral accessory protein Vpx.. Cell host & microbe, 2012.
- Sun S, Zhang Z, Fregoso O, Krainer AR. Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2.. RNA (New York, N.Y.), 2011.
- Bish RA, Fregoso OI, Piccini A, Myers MP. Conjugation of complex polyubiquitin chains to WRNIP1.. Journal of proteome research, 2008.
- Llano M, Vanegas M, Fregoso O, Saenz D, Chung S, Peretz M, Poeschla EM. LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes.. Journal of virology, 2004.