A quality control pathway that down-regulates aberrant T-cell receptor (TCR) transcripts by a mechanism requiring UPF2 and translation.
Nonsense-mediated decay (NMD) is an RNA surveillance pathway that degrades mRNAs containing premature termination codons (PTC). T-cell receptor (TCR) and immunoglobulin (Ig) transcripts, which are encoded by genes that very frequently acquire PTCs during lymphoid ontogeny, are down-regulated much more dramatically in response to PTCs than are other known transcripts. Another feature unique to TCR, Ig, and a subset of other mRNAs is that they are down-regulated in response to nonsense codons in the nuclear fraction of cells. This is paradoxical, as the only well recognized entity that recognizes nonsense codons is the cytoplasmic translation apparatus. Therefore, we investigated whether translation is responsible for this nuclear-associated mechanism. We found that the down-regulation of TCR-beta transcripts in response to nonsense codons requires several features of translation, including an initiator ATG and the ability to scan. We also found that optimal down-regulation depends on a Kozak consensus sequence surrounding the initiator ATG and that it can be initiated by an internal ribosome entry site, neither of which has been demonstrated before for any other PTC-bearing mRNA. At least a portion of this down-regulatory response is mediated by the NMD pathway as antisense hUPF2 transcripts increased the levels of PTC-bearing TCR-beta transcripts in the nuclear fraction of cells. We conclude that a hUPF2-dependent RNA surveillance pathway with translation-like features operating in the nuclear fraction of cells prevents the expression of potentially deleterious truncated proteins encoded by non-productively rearranged TCR genes.
Wang
Jun
J
Department of Immunology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Vock
Vita M
VM
Li
Shulin
S
Olivas
O Renee
OR
Wilkinson
Miles F
MF
D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence; D018389:Codon, Nonsense; D017931:DNA Primers; D015536:Down-Regulation; D005656:Fungal Proteins / Q000235:genetics / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D010957:Plasmids; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D018389:Codon, Nonsense; D017931:DNA Primers; D005656:Fungal Proteins; C092470:NMD2 protein, S cerevisiae; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators