Two groups have recently disrupted the murine Trim21 gene, encoding a protein known as the lupus autoantigen Ro52 (1, 2). They report strikingly different phenotypes for their knockout mice. These differences may cause considerable confusion in the field as to the true outcome of Trim21 gene disruption. The Trim21−/− mice described by us live a normal life span with no overt abnormal phenotypes (1). Their immune cells show normal composition and comparable responses to pathogen signals and Ag stimulation as those of wild-type mice, with the exception of enhanced production of some cytokines in fibroblasts. Several TRIM proteins encoded near Trim21 were found up-regulated in Trim21−/− cells, leading us to conclude that the absence of TRIM21 protein in these mice was compensated by a network of cross-talk among related TRIM members. In contrast, Espinosa et al., reported that mice with a disrupted Trim21 gene developed a profound lupus-like disease initiated by an injury from ear tagging, along with abnormal cytokine responses involving the Th17 pathway (2). This phenotype was baffling to us, because we did not observe a single example of ear tag-induced inflammation. There are marked differences in the gene disruption method used by the two groups, some of which may account for the dissimilar phenotypes of the two knockouts (Fig. 1). First, it is possible that the PGK-neo cassette retained in the mice by Espinosa (Fig. 1 B) could be responsible for the inflammatory disease phenotype, because a PGK-neo cassette can have profound effects on the function of endogenous linked genes (3, 4). This possibility is significant, as Trim21 on chromosome 6 is flanked by a number of genes with immunological activities. Second, the retention of exons 1–4 in these mice may lead to the expression of a truncated protein as a result of translation from the ATG in exon 3. A truncated protein of this nature would carry the RING domain with E3 ubiquitin ligase activity plus the B-box and part of the coiled-coil domain. Although the possibility that environmental differences between the colonies of the two laboratories could account for the discrepancies cannot be ruled out, we feel it is important to determine whether the presence of the PGK-neo cassette and/or a truncated TRIM21 protein might explain an aberrant inflammatory phenotype.
Comment on “Gene Disruption Study Reveals a Nonredundant Role for TRIM21/Ro52 in NF-κB-Dependent Cytokine Expression in Fibroblasts”
Keiko Ozato, Ryusuke Yoshimi, Tsung-Hsien Chang, Hongsheng Wang, Toru Atsumi, Herbert C. Morse; Comment on “Gene Disruption Study Reveals a Nonredundant Role for TRIM21/Ro52 in NF-κB-Dependent Cytokine Expression in Fibroblasts”. J Immunol 15 December 2009; 183 (12): 7619. https://doi.org/10.4049/jimmunol.0990103
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