title: A novel post-translational modification of nucleolin, SUMOylation at Lys-294, mediates arsenite-induced cell death by regulating gadd45α mRNA stability.
abstract: Nucleolin is a ubiquitously expressed protein and participates in many important biological processes, such as cell cycle regulation and ribosomal biogenesis. The activity of nucleolin is regulated by intracellular localization and post-translational modifications, including phosphorylation, methylation, and ADP-ribosylation. Small ubiquitin-like modifier (SUMO) is a category of recently verified forms of post-translational modifications and exerts various effects on the target proteins. In the studies reported here, we discovered SUMOylational modification of human nucleolin protein at Lys-294, which facilitated the mRNA binding property of nucleolin by maintaining its nuclear localization. In response to arsenic exposure, nucleolin-SUMO was induced and promoted its binding with gadd45α mRNA, which increased gadd45α mRNA stability and protein expression, subsequently causing GADD45α-mediated cell death. On the other hand, ectopic expression of Mn-SOD attenuated the arsenite-generated superoxide radical level, abrogated nucleolin-SUMO, and in turn inhibited arsenite-induced apoptosis by reducing GADD45α expression. Collectively, our results for the first time demonstrate that nucleolin-SUMO at K294R plays a critical role in its nucleus sequestration and gadd45α mRNA binding activity. This novel biological function of nucleolin is distinct from its conventional role as a proto-oncogene. Therefore, our findings here not only reveal a new modification of nucleolin protein and its novel functional paradigm in mRNA metabolism but also expand our understanding of the dichotomous roles of nucleolin in terms of cancer development, which are dependent on multiple intracellular conditions and consequently the appropriate regulations of its modifications, including SUMOylation.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987 and; Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987 and.
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Qipeng
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987 and.
authors.forename: Guangxun
authors.initials: G
authors.lastname: Gao
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Wei
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Haishan
authors.initials: H
authors.lastname: Huang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987 and.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Jimin
authors.initials: J
authors.lastname: Gao
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987 and. Electronic address: chuanshu.huang@nyumc.org.
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D016475:3T3 Cells; D000818:Animals; D018053:Arsenites / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000235:genetics; D000090063:Proto-Oncogene Mas; D020871:RNA Stability / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation / Q000187:drug effects* / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013723:Teratogens / Q000494:pharmacology*; D000097796:Nucleolin; D000097642:GADD45 Proteins
chemical_list: D018053:Arsenites; D018797:Cell Cycle Proteins; D008239:Lysine; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D013482:Superoxide Dismutase; D013723:Teratogens; D000097796:Nucleolin; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C499072:Gadd45a protein, mouse; C000715470:MAS1 protein, human; C015001:arsenite
keywords: Apoptosis; Metal; Nucleolus; Oxidative Stress; Small Ubiquitin-like Modifier (SUMO)