RNF166 plays a dual role for Lys63-linked ubiquitination and sumoylation of its target proteins

Ih Yeon Hwang, Chang Ki Oh, Young Ki Choi, Nuri Yun, Young J. Oh

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Ubiquitination and sumoylation are two important posttranslational modifications in cells. RING (Really Interesting New Gene)-type E3 ligases play essential roles in regulating a plethora of biological processes such as cell survival and death. In our previous study, we performed a microarray using inputs from MN9D dopaminergic neuronal cells treated with 6-hydroxydopamine and identified a novel RING-type E3 ligase, RNF166. We showed that RNF166 exerts proapoptotic effects via ubiquitin-dependent degradation of X-linked inhibitor of apoptosis and subsequent overactivation of caspase-dependent neuronal death following 6-hydroxydopamine treatment. In the present study, we further expanded the list of RNF166’s binding substrates using mass spectral analyses of immunoprecipitates obtained from RNF166-overexpressing HEK293 cells. Poly (ADP-ribose) polymerase 1, ATPase WRNIP1, X-ray repair cross-complementing protein 5 (Ku80), and replication protein A 70 were identified as potential binding partners of RNF166. Additionally, we confirmed that RNF166 interacts with and forms lysine 63-linked polyubiquitin chains in Ku80. Consequently, these events promoted the increased stability of Ku80. Intriguingly, we found that RNF166 also contains distinct consensus sequences termed SUMO-interacting motifs and interacts with apoptosis signal-regulating kinase 1 (ASK1). We determined that RNF166 induces the sumoylation of ASK1. Overall, our data provide novel evidence that RNF166 has a dual function of Lys63-linked ubiquitination and sumoylation of its cellular targets.

Original languageEnglish
Pages (from-to)463-475
Number of pages13
JournalJournal of Neural Transmission
Issue number5-6
Publication statusPublished - 2022 Jun

Bibliographical note

Funding Information:
This work was supported by the Brain Research Program (2017M3C7A10253369 to YJO) and by the Mid-Career Research Program (2019R1A2C1088793 to YJO) through the National Research Foundation (NRF) of Korea funded by Ministry of Science and ICT, and by the Small Grant for Exploratory Research program (2018R1D1A1A02085731 to NY) and by Basic Science Research Program (2021R1I1A1A01047405 to NY) through the NRF funded by the Ministry of Education.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry


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