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Unfolded protein response (UPR) is a cytoprotective mechanism activated during various stresses. Its most conserved branch is represented by the IRE/XBP1 pathway. The hallmark of this pathway is the unconventional IRE1-dependent cytoplasmic splicing of XBP1 mRNA. The spliced mRNA encodes a potent transcription factor, which activates protein degradation. Different viruses are known to activate this pathway, presumably to promote viral propagation. In this study, we have demonstrated that the members of Picornaviridae family are able to inhibit the IRE1/XBP1 pathway. In particular, this defense mechanism was suppressed in HeLa cells infected with poliovirus, encephalomyocarditis virus (EMCV), or coxsackievirus B3. Upon chemical induction of UPR (by dithiothreitol, tunicamycin, or thapsighargin), significantly lower levels of spliced XBP1 mRNA were detected in infected than in non-infected cells. The levels of IRE1 endonuclease were shown to decrease during the lifecycle of poliovirus and EMCV. While inhibition of XBP1 mRNA splicing occurred in cells infected with wild-type EMCV, it was not observed upon infection with an EMCV mutant with altered anti-defensive (“security”) leader protein. Thus, we have demonstrated that the picornaviruses can suppress the development of IRE1/Xbp1 defensive mechanism and that viral security proteins may have a major role in this counteraction.