Cell autonomous responses to intracellular bacteria largely depend on gene expression reorganization. To gain isoform-level resolution into these regulations, we combined long- and short-read transcriptomic analysis of the response of intestinal epithelial cells to infection by the foodborne pathogenListeria monocytogenes(Lm). Expression of the cellular stress response regulator CIRBP (cold-inducible RNA-binding protein) switched from a canonical transcript to a nonsense-mediated decay-sensitive isoform. Permeation of host cell membranes by bacterial pore-forming toxins such as Lm-secreted listeriolysin O drove CIRBP alternative splicing via CLK1 inhibition and dephosphorylation of serine/arginine-rich (SR) splicing factors, similarly to a previously reported pathway upon heat stress. Selective repression of canonical CIRBP dampened infection while that of the alternative isoform exacerbated it. Consistently, CIRBP-bound RNA targets were shifted towards stress-relevant transcripts upon infection. CIRBP alternative splicing can thus be generalized as a common response to biotic or abiotic stresses also relevant in the context of bacterial infection.
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