Acid stress causes resistance to acetic acid-induced regulated cell death (AA-RCD) in budding yeast, resulting in catalase activation. In order to explore the molecular determinants of evasion of AA-RCD triggered by acid stress adaptation, we studied the involvement and the possible interplay of the master regulator of transcription high-osmolarity glycerol 1 (HOG1) andRTG2, a positive regulator of theRTG-dependent mitochondrial retrograde signaling. Viability, DNA fragmentation, and ROS accumulation have been analyzed in wild-type and mutant cells lackingHOG1and/orRTG2. Catalase activity and transcription ofCTT1andCTA1, coding the cytosolic and peroxisomal/mitochondrial catalase, respectively, as well asHog1phosphorylation, were also analyzed. Our results show thatHOG1is essential for resistance to AA-RCD and its activation results in the upregulation ofCTT1, but notCTA1, transcription during acid stress adaptation.RTG2is required forHog1-dependentCTT1upregulation upon acid stress, despite failure ofRTGpathway activation. We give evidence thatRtg2has a cytoprotective role and can act as a general cell stress sensor independent of Rtg1/3-dependent transcription.