title: Nuclear Phosphoproteomic Screen Uncovers ACLY as Mediator of IL-2-induced Proliferation of CD4+ T lymphocytes.
abstract: Anti-cancer immunotherapies commonly rely on the use of interleukin-2 (IL-2) to promote the expansion of T lymphocytes. IL-2- dependent proliferation is the culmination of a complex network of phosphorylation-driven signaling events that impact on gene transcription through mechanisms that are not clearly understood. To study the role of IL-2 in the regulation of nuclear protein function we have performed an unbiased mass spectrometry-based study of the nuclear phosphoproteome of resting and IL-2-treated CD4(+) T lymphocytes. We detected 8521distinct phosphosites including many that are not yet reported in curated phosphorylation databases. Although most phosphorylation sites remained unaffected upon IL-2 treatment, 391 sites corresponding to 288 gene products showed robust IL-2-dependent regulation. Importantly, we show that ATP-citrate lyase (ACLY) is a key phosphoprotein effector of IL-2-mediated T-cell responses. ACLY becomes phosphorylated on serine 455 in T lymphocytes upon IL-2-driven activation of AKT, and depletion or inactivation of ACLY compromises IL-2-promoted T-cell growth. Mechanistically, we demonstrate that ACLY is required for enhancing histone acetylation levels and inducing the expression of cell cycle regulating genes in response to IL-2. Thus, the metabolic enzyme ACLY emerges as a bridge between cytokine signaling and proliferation of T lymphocytes, and may be an attractive candidate target for the development of more efficient anti-cancer immunotherapies.
authors.affiliation: From the ‡Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark;
authors.forename: Nerea
authors.initials: N
authors.lastname: Osinalde
authors.affiliation: §Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, UPV/EHU, 48940 Leioa, Spain;
authors.forename: Jone
authors.initials: J
authors.lastname: Mitxelena
authors.affiliation: From the ‡Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark;
authors.forename: Virginia
authors.initials: V
authors.lastname: Sánchez-Quiles
authors.affiliation: From the ‡Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark;
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Akimov
authors.affiliation: ¶Proteomics Core Facility-SGIKER, University of the Basque Country, UPV/EHU, 48940 Leioa, Spain;
authors.forename: Kerman
authors.initials: K
authors.lastname: Aloria
authors.affiliation: ‖Department of Biochemistry and Molecular Biology, University of the Basque Country, UPV/EHU, 48940 Leioa, Spain.
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Arizmendi
authors.affiliation: §Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, UPV/EHU, 48940 Leioa, Spain;
authors.forename: Ana M
authors.initials: AM
authors.lastname: Zubiaga
authors.affiliation: From the ‡Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark;
authors.forename: Blagoy
authors.initials: B
authors.lastname: Blagoev
authors.affiliation: From the ‡Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; ihk@bmb.sdu.dk.
authors.forename: Irina
authors.initials: I
authors.lastname: Kratchmarova
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000302:isolation & purification*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000032:analysis / Q000187:drug effects; D010750:Phosphoproteins / Q000032:analysis / Q000187:drug effects; D040901:Proteomics / Q000379:methods*
chemical_list: D007376:Interleukin-2; D009687:Nuclear Proteins; D010750:Phosphoproteins; D001275:ATP Citrate (pro-S)-Lyase