Abstract: Perturbations in secretory function activate stress response pathways critical for yeast survival. Here we report the identification of the Hos2p/Set3p deacetylase complex (SET3C) as an essential component of the secretory stress response. Strains lacking core components of the Hos2p/Set3p complex exhibit hyper-sensitivity to secretory stress. Although not required for the unfolded protein response (UPR) and ribosomal gene repression, the Hos2p-complex is required for proper activation of the Mpk1p/Slt2p cell integrity kinase cascade. Disruption of the Hos2p complex results in abrogated Mpk1p phosphorylation, whereas constitutive activation of the Mpk1p pathway rescues the hos2Delta growth defect in response to secretory stress. Furthermore, Hos2p activity is required for Mpk1p-mediated activation of the stress-responsive transcription factor Rlm1p, but not for the stress-induced degradation of the C-type cyclin Ssn8p. Our results identify the Hos2p complex as a critical component in the secretory stress response and support the existence a coordinated stress response consisting of the UPR, ribosomal gene repression and MAP kinase signaling in response to defects in secretory function.