O-GlcNAcylation of RBM14 contributes to elevated cellular O-GlcNAc through regulation of OGA protein stability
Tae Hyun Kweon,
Hyeryeon Jung,
Jeong Yeon Ko,
Jingu Kang,
Wonyoung Kim,
Yeolhoe Kim,
Han Byeol Kim,
Eugene C. Yi,
Nam-On Ku,
Jin Won Cho,
Won Ho Yang
Affiliations
Tae Hyun Kweon
Interdisciplinary Program of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul 03722, Republic of Korea; Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
Hyeryeon Jung
Department of Molecular Medicine and Biopharmaceutical Sciences, School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul 03080, Republic of Korea
Jeong Yeon Ko
Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
Jingu Kang
Interdisciplinary Program of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul 03722, Republic of Korea; Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
Wonyoung Kim
Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
Yeolhoe Kim
Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
Han Byeol Kim
Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
Eugene C. Yi
Department of Molecular Medicine and Biopharmaceutical Sciences, School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul 03080, Republic of Korea
Nam-On Ku
Interdisciplinary Program of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul 03722, Republic of Korea
Jin Won Cho
Interdisciplinary Program of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul 03722, Republic of Korea; Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea; Corresponding author
Won Ho Yang
Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea; Corresponding author
Summary: Dysregulation of O-GlcNAcylation has emerged as a potential biomarker for several diseases, particularly cancer. The role of OGT (O-GlcNAc transferase) in maintaining O-GlcNAc homeostasis has been extensively studied; nevertheless, the regulation of OGA (O-GlcNAcase) in cancer remains elusive. Here, we demonstrated that the multifunctional protein RBM14 is a regulator of cellular O-GlcNAcylation. By investigating the correlation between elevated O-GlcNAcylation and increased RBM14 expression in lung cancer cells, we discovered that RBM14 promotes ubiquitin-dependent proteasomal degradation of OGA, ultimately mediating cellular O-GlcNAcylation levels. In addition, RBM14 itself is O-GlcNAcylated at serine 521, regulating its interaction with the E3 ligase TRIM33, consequently affecting OGA protein stability. Moreover, we demonstrated that mutation of serine 521 to alanine abrogated the oncogenic properties of RBM14. Collectively, our findings reveal a previously unknown mechanism for the regulation of OGA and suggest a potential therapeutic target for the treatment of cancers with dysregulated O-GlcNAcylation.
