Widespread JNK-dependent alternative splicing induces a positive feedback loop through CELF2-mediated regulation of MKK7 during T-cell activation.
Alternative splicing is prevalent among genes encoding signaling molecules; however, the functional consequence of differential isoform expression remains largely unknown. Here we demonstrate that, in response to T-cell activation, the Jun kinase (JNK) kinase MAP kinase kinase 7 (MKK7) is alternatively spliced to favor an isoform that lacks exon 2. This isoform restores a JNK-docking site within MKK7 that is disrupted in the larger isoform. Consistently, we show that skipping of MKK7 exon 2 enhances JNK pathway activity, as indicated by c-Jun phosphorylation and up-regulation of TNF-α. Moreover, this splicing event is itself dependent on JNK signaling. Thus, MKK7 alternative splicing represents a positive feedback loop through which JNK promotes its own signaling. We further show that repression of MKK7 exon 2 is dependent on the presence of flanking sequences and the JNK-induced expression of the RNA-binding protein CELF2, which binds to these regulatory elements. Finally, we found that ∼25% of T-cell receptor-mediated alternative splicing events are dependent on JNK signaling. Strikingly, these JNK-dependent events are also significantly enriched for responsiveness to CELF2. Together, our data demonstrate a widespread role for the JNK-CELF2 axis in controlling splicing during T-cell activation, including a specific role in propagating JNK signaling.
['Martinez|Nicole M|NM|', 'Agosto|Laura|L|', 'Qiu|Jinsong|J|', 'Mallory|Michael J|MJ|', 'Gazzara|Matthew R|MR|', 'Barash|Yoseph|Y|', 'Fu|Xiang-Dong|XD|', 'Lynch|Kristen W|KW|']
D017398:Alternative Splicing D015496:CD4-Positive T-Lymphocytes D000067878:CELF Proteins D025461:Feedback, Physiological D005786:Gene Expression Regulation D006801:Humans D048031:JNK Mitogen-Activated Protein Kinases D019169:Jurkat Cells D048688:MAP Kinase Kinase 7 D009419:Nerve Tissue Proteins D020871:RNA Stability D015398:Signal Transduction D013601:T-Lymphocytes
alternative splicing positive feedback MKK7 JNK CELF2