Title:
Novel mRNA and Protein quality control systems induced by aberrant translation in eukaryotes
Toshifumi INADA, Ph.D.
Professor
Graduate School of Pharmaceutical Sciences,Z
Tohoku University
Abstract:
Cells have mRNA surveillance systems to recognize aberrant translation elongation and termination, and eliminate aberrant mRNAs. NMD (Nonsense-Mediated mRNA Decay) is the most characterized mRNA surveillance system that recognizes and eliminates aberrant mRNAs containing a premature termination codon (PTC). NSD (NonStop Decay) system rapidly degrades nonstop mRNA that lacks a termination codon and is produced mainly by polyadenylation within an ORF. NGD (No-Go Decay) quality control system recognize s the stalling of ribosomes during translational elongation and induces endonucleolytic cleavage of the mRNA in the vicinity of the stalled site that leads to rapid mRNA degradation.
We have recently demonstrated that rapid proteasomal degradation of aberrant proteins derived from aberrant mRNAs plays an important role in preventing the expression of abnormal proteins as well as in promoting rapid mRNA decay by mRNA surveillance systems. In NSD and NGD , translation arrest induced by a nascent peptide with positively charged residues results in co-translational degradation of the arrested protein product by the proteasome ( EMBO J. 2005;Genes Dev , 2007; EMBO Rep . 2010 ), and two distinct E3 ubiquitin ligases and novel factors including Rqc1, Tae2 and Cdc48, that interact with 60S ribosomal subunit are involved in the degradation of arrest products associated with stalled ribosome ( JBC , 2009; Cell , 2012 ) . We also found that Dom34:Hbs1 stimulates degradation of stop-codon-less and nonstop mRNAs by dissociating a ribosome that is stalled at the 3′ end of the mRNA , which makes the released mRNA more vulnerable to nucleolytic attack, and that Dom34:Hbs1 plays important roles in both NSD and NGD ( PNAS , 2010; Mol. Cell , 2012). I will also present recent results about a novel role of E3 ubiquitin ligase Hel2 in the endonucleolytic cleavage of the mRNA in NGD.
References:
1. “ Dom34:Hbs1 Plays a General Role in Quality Control Systems by Dissociation of Stalled Ribosome at 3′ End of Aberrant mRNA ” T. Tsuboi, K. Kuroha, K. Kudo, S. Makino, E. Inoue, I. Kashima and T. Inada Mol. Cell, 26, 518-529 (2012).
2. “ A ribosome-bound quality control complex triggers nascent peptides and signals translation stress ” O. Brandman, JS. Ornstein, D. Wong, A. Larson, C.C. Williams, G.W. Li, S. Zhou, D. King, P.S. Shen, J. Weibezahn, J.G. Dunn, S. Rouskin, T. Inada , A. Frost, JS. Weissman
Cell, 151, 1042-1054 (2012).
3. “ RACK1 stimulates nascent polypeptide-dependent translation arrest ” K. Kuroha, M. Akamatsu, L. Dimitrova, T. Ito, Y. Kato, K. Shirahige and T. Inada EMBO Reports, 11, 956-961 (2010).
4. “ Structural Basis for mRNA Surveillance by Archaeal Pelota and GTP-bound EF1α Complex ” K. Kobayashi, I. Kikuno, K. Kuroha, K. Saito, K. Ito, R. Ishitani, T. Inada and O. Nureki
Proc. Natl. Acad. Sci. USA, 107, 17575-17579 (2010).
5. “ Nascent peptide-dependent translation arrest leads to not4p-mediated protein degradation by the proteasome ” K. Kuroha, L. Dimitrova, T. Tatematsu and T. Inada J. Biol. Chem ., 284 , 10343-10352 (2009).
6. “Translation of poly(A) tail plays crucial roles in nonstop mRNA surveillance via translation repression and protein destabilization by proteasome in yeast” S. Ito-Harashima, K. Kuroha, T. Tatematsu and T. Inada Genes Dev ., 21 , 519-524 (2007).
7. “Translation of aberrant mRNAs lacking a termination codon or with a shortened 3′-UTR is repressed after initiation in yeast” T. Inada * and H. Aiba EMBO J., 24 , 1584-1595 (2005).
