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Originally published In Press as doi:10.1074/jbc.M111781200 on March 11, 2002

J. Biol. Chem., Vol. 277, Issue 21, 18489-18493, May 24, 2002
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A Quality Control Pathway That Down-regulates Aberrant T-cell Receptor (TCR) Transcripts by a Mechanism Requiring UPF2 and Translation*

Jun Wang, Vita M. Vock, Shulin Li, O. Renee Olivas, and Miles F. WilkinsonDagger

From the Department of Immunology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

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.

* This work was supported by National Institutes of Health Grant GM 58595 and National Science Foundation Grant MCB-9808936.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Immunology, Box 180, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-794-5526; Fax: 713-745-0846; E-mail: mwilkins@mail.mdanderson.org.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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