The ubiquitin-directed AAA-ATPase VCP/p97 facilitates degradation of misfolded proteins in diverse cellular stress response pathways. Resolving the complexity of dynamic interactions with hosts of accessory proteins and substrates has therefore been a major challenge. Here, we used affinity-purification SWATH mass spectrometry (AP-SWATH) to identify proteins that specifically interact with a p97 substrate-trapping mutant, p97-E578Q. AP-SWATH identified differential interactions over a large detection range from abundant cofactors to pathway-specific partners and individual ligases such as RNF185 and MUL1 that were trapped in p97-E578Q complexes. In addition, we identified substrate candidates including the PP1 regulator CReP/PPP1R15B that dephosphorylates eIF2α and thus counteracts attenuation of translation by stress-kinases. We demonstrate here that p97 with its Ufd1-Npl4 adapter ensures rapid turnover and balanced levels of CReP in unperturbed cells. Moreover, we show that p97 is essential for the quantitative stress-induced degradation of CReP and, consequently, robust eIF2α phosphorylation to enforce the stress response. Thus, p97 not only facilitates bulk degradation of misfolded proteins upon stress, but also has an unanticipated function in directly modulating the integrated stress response at the level of signalling.