title: AG490 and PF431396 Sensitive Tyrosine Kinase Control the Population Heterogeneity of Basal STAT1 Activity in Ube1l Deficient Cells.
abstract: A population often contains distinct sub-populations, thereby increasing the complexity of the overall heterogeneity. However, the cellular origin and biological relevance of sub-populations in cell population have not been clearly identified. Here we demonstrated the novel roles of ISGylation, which is an IFN-induced post-translational modification, controlling heterogeneity at the population level in cultured adherent cells. Without UBE1L, an E1 enzyme of ISGylation, mouse embryonic fibroblasts (MEF) exhibited low viral resistance despite high STAT1 and ISG expression compared with the wild-type MEF. We observe that Ube1l-/- MEF populations consist of two behaviorally distinguishable sub-populations with distinct basal STAT1 activity, while wild-type MEF populations are unimodal. This population heterogeneity in Ube1l knock-out cells was perturbed by tyrosine kinase inhibitors, AG490 and PF431396. In contrast, the neutralization of type I IFN did not affect population heterogeneity. Based on these results, we concluded that UBE1L functions to adjust basal immunological states with the regulation of population heterogeneity.
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.
authors.forename: Hesung
authors.initials: H
authors.lastname: Now
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Yoo
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D018345:Mice, Knockout; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes; D020032:Tyrphostins / Q000494:pharmacology; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics* / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; C489550:G1p2 protein, mouse; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D020032:Tyrphostins; D014452:Ubiquitins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D011505:Protein-Tyrosine Kinases; C534879:UBA7 protein, human; D044764:Ubiquitin-Activating Enzymes