GANP may reulates the c-Myc expression in germinal center (GCs), that is essential for the affinity maturation of B cells)

• Project/Area Number: 19K16691
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Osaka University
• Principal Investigator: SINGH SHAILENDRA KUMAR 大阪大学, 免疫学フロンティア研究センター, 特任研究員(常勤) (10792187)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: GANP / c-Myc / eIF4E / Germinal center / immune regulation / Acquired immunity / Immune Regulation

Outline of Research at the Start

GANP was found as an up regulated molecule in GC B cells. We identified, GANP is associated with the eIF4E complex and c-Myc mRNA in B cells. c-Myc is critical for GC B cell selection and survival. GANP might play a novel role for eIF4E-sensitive mRNA metabolism and c-Myc regulation in GC B cells.

Outline of Final Research Achievements

Germinal Center (GC)-associated nuclear protein (GANP) was discovered as up-regulated molecule in GC B cells upon T cell dependent immune responses, GANP-deficient mice failed to generate affinity-maturation of Ag-specific antibodies in B cells thus; GANP is critical molecule for the regulation of adaptive immune system.
We investigated mRNAs and proteins associated with GANP in B cells. GANP interacts with many kinds of RNAs for various functions of cancer development, cell cycling, DNA repair, and protein translation. GANP interacts with the translation initiation factor eIF4E and efficiently targets the transcription factor c-Myc mRNA. Furthermore, GANP regulates c-Myc translation via interacting with the 5’ untranslated region of c-Myc mRNA in B cells. The results indicated that GANP is necessary for the upregulation of c-Myc in B cells undergoing the selection process in the GCs. The augmented c-Myc expression by GANP is likely a regulatory signal for B cell positive selection.

Academic Significance and Societal Importance of the Research Achievements

Our studies suggest that GANP regulates the c-Myc mRNA in cooperation with translation initiation factor eIF4E, for the positive selection of high affinity GC B cells during immune responses. Our research direction holds great promise for the discovery of new targets for therapeutic applications.

Research Products

• [Journal Article] Feedback regulation of Arid5a and Ppar-γ2 maintains adipose tissue homeostasis (2019)
  • Author(s): Chalise Jaya Prakash、Hashimoto Shigeru、Parajuli Gyanu、Kang Sujin、Singh Shailendra Kumar、Gemechu Yohannes、Metwally Hozaifa、Nyati Kishan Kumar、Dubey Praveen Kumar、Zaman Mohammad Mahabub-Uz、Nagahama Yasuharu、Hamza Hanieh、Masuda Kazuya、Kishimoto Tadamitsu
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 116 Issue: 30 Pages: 15128-15133
  • DOI: 10.1073/pnas.1906712116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism. (2019)
  • Author(s): Sakaguchi M, Cai W, Wang CH, Cederquist CT, Damasio M, Homan EP, Batista T, Ramirez AK, Gupta MK, Steger M, Wewer Albrechtsen NJ, Singh SK, Araki E, Mann M, Enerback S, Kahn CR.
  • Journal Title: Nat Commun. Volume: 10 Issue: 1 Pages: 1582-1582
  • DOI: 10.1038/s41467-019-09418-0
  • Peer Reviewed / Open Access / Int'l Joint Research