Title:
Ribosome stalling-mediated ubiquitination is a beacon to induce quality controls

 

Speaker:
Toshifumi Inada
Tohoku University, Graduate School of Pharmaceutical Sciences, Sendai, Japan

 

Abstract:
Accurate translation is a prerequisite for all cellular processes. Cells defense their proteome from erroneous products whose accumulation induces stress responses and the failed clearance causes an increasingly broad range of protein-misfolding diseases. The numerous diseases are associated with remarkably subtle deviations of many translation components. For instance, the defective editing activity of a single tRNA synthetase or the mutation of only one isoacceptor tRNA out of six in mice can predispose cells toward ribosome stalling and neurodegeneration1. Ribosome stalling-mediated ubiquitination is a beacon to induce Ribosome-associated protein Quality Control (RQC) to eliminate the aberrant nascent polypeptide2-6. An E3 ubiquitin ligase Hel2/ZNF598 recognizes the adjacent stalled ribosomes composed of the leading ribosome, and the following ribosomes road-blocked by the leading ribosome7-9. Hel2/ZNF598 forms K63-linked polyubiquitin chain on 40S ribosomal protein uS10, RQT (RQC-trigger factor) complex subsequently recognizes the ubiquitinated ribosomes and dissociates into subunits7. The aberrant peptidyl-tRNA on the 60S subunit is subjected to Ltn1-mediated proteasomal-degradation10,11.
The ubiquitin is also a beacon for abnormal translation induced by a non-functional ribosome itself. The mutant ribosome with the mutation in the decoding center of 18S rRNA is subjected to 18S Non-functional rRNA Decay (NRD) quality control that requires K63-linked polyubiquitination of 40S ribosomal protein uS312. We propose general functions of ribosome ubiquitination in quality controls for aberrant translation.

 

References:
1. Ishimura, R. et al. RNA function. Science 345, 455-9 (2014).
2. Brandman, O. & Hegde, R.S. Nat Struct Mol Biol 23, 7-15 (2016).
3. Inada, T. Trends Biochem Sci 42, 5-15 (2017).
4. Ito-Harashima, S. et al. Genes Dev 21, 519-24 (2007).
5. Dimitrova, L.N., et al. J Biol Chem 284, 10343-52 (2009).
6. Tsuboi, T. et al. Mol Cell 46, 518-29 (2012).
7. Matsuo, Y. et al. Nat Commun 8, 159 (2017).
8. Sundaramoorthy, E. et al. Mol Cell 65, 751-760 e4 (2017).
9. Ikeuchi, K. et al. EMBO J 38(2019).
10. Joazeiro, C.A.P. M Nat Rev Mol Cell Biol 20, 368-383 (2019).
11. Su, T., Izawa, T., et al. Nature (2019).
12. Sugiyama, T. et al. Cell Rep 26, 3400-3415.e7 (2019).