Diversity in cap-binding translation factor complexes: roles in translation initiation and mechanisms of mRNA selection

• Applicant: Professorin Dr. Christine Elizabeth Clayton
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Biochemistry ; Cell Biology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 419208155

• Final Report Year: 2023

Final Report Abstract

We have made substantial progress in determining the roles of the different EIF4E complexes: All of our evidence indicates that in T. brucei, EIF4E1 is solely a translational repressor, with activity depending on the association with 4EIP. We uncovered a completely novel role for EIF4E2 in stabilising S-phase mRNAs. EIF4E4/EIF4G3 has a specific role in translating mRNAs encoding ribosomal proteins and requires EIF4A1 for function. EIF4E5 is needed only in procyclic forms; mRNAs bound to the complex component RBP43 implicate the complex in EP procyclin synthesis. EIF4E6/EIF4G5 and EIF4E3/EIF4G4 are both implicated in general translation, but in bloodstream forms the EIF4E6/EIF4G5 complex is specialized towards translation of mRNAs associated with the MKT complex. The role of EIF4E6/EIF4G5 in procyclic forms is less clear since no association with the MKT complex or other translation-related proteins was detected.

Publications

• The RNA-associated proteins MKT1 and MKT1L form alternative PBP1-containing complexes in Trypanosoma brucei. Journal of Biological Chemistry, 295(32), 10940-10955.
  Melo, do Nascimento Larissa; Terrao, Monica; Marucha, Kevin Kamanyi; Liu, Bin; Egler, Franziska & Clayton, Christine
  
• Functional insights from a surface antigen mRNA-bound proteome. eLife, 10.
  Melo, do Nascimento Larissa; Egler, Franziska; Arnold, Katharina; Papavasiliou, Nina; Clayton, Christine & Erben, Esteban
  
• The EIF4E1-4EIP cap-binding complex of Trypanosoma brucei interacts with the terminal uridylyl transferase TUT3. PLOS ONE, 16(11), e0258903.
  Falk, Franziska; Kamanyi, Marucha Kevin & Clayton, Christine
  
• Distinct mRNA and protein interactomes highlight functional differentiation of major eIF4F-like complexes from Trypanosoma brucei. Frontiers in Molecular Biosciences, 9.
  Bezerra, Maria J. R.; Moura, Danielle M. N.; Freire, Eden R.; Holetz, Fabiola B.; Reis, Christian R. S.; Monteiro, Tallyta T. S.; Pinto, Adriana R. S.; Zhang, Ning; Rezende, Antonio M.; Pereira-Neves, Antonio; Figueiredo, Regina C. B. Q.; Clayton, Christine; Field, Mark C.; Carrington, Mark & de Melo Neto Osvaldo, P.
  
• Roles and interactions of the specialized initiation factors EIF4E2, EIF4E5, and EIF4E6 in Trypanosoma brucei: EIF4E2 maintains the abundances of S‐phase mRNAs. Molecular Microbiology, 118(4), 457-476.
  Falk, Franziska; Melo, Palhares Rafael; Waithaka, Albina & Clayton, Christine
  
• Structural analysis of the Trypanosoma brucei EIF4E6/EIF4G5 complex reveals details of the interaction between unusual eIF4F subunits. Scientific Reports, 14(1).
  Penteado, Renato Ferras; da Silva, Renata Santana; Moura, Danielle Maria Nascimento; de Lima, Gustavo Barbosa; Malvezzi, Amaranta Muniz; Monteiro, Tallyta Tâmara da Silva; Xavier, Camila Cavalcanti; Vichier-Guerre, Sophie; Dugué, Laurence; Pochet, Sylvie; Zanchin, Nilson Ivo Tonin; Reis, Christian Robson de Souza; de Melo, Neto Osvaldo Pompílio & Guimarães, Beatriz Gomes
  
• Distinct modes of interaction within eIF4F-like complexes and susceptibility to the RocA inhibitor for the Trypanosoma brucei EIF4AI translation initiation factor. PLOS One, 20(5), e0322812.
  Moura, Danielle M. N.; Soares, Amanda L.; da, Silva Adalúcia; Ribeiro, João L. A. B.; Sunter, Jack D.; Assis, Ludmila A.; Carrington, Mark & de Melo Neto Osvaldo, P.