Endoplasmic reticulum-associated degradation (ERAD) disposes of aberrant 
proteins in the secretory pathway. Protein substrates of ERAD are dislocated via 
the Sec61p translocon from the endoplasmic reticulum to the cytosol, where they 
are ubiquitinated and degraded by the proteasome. Since the Sec61p channel is 
also responsible for import of nascent proteins, this bidirectional passage 
should be coordinated, probably by molecular chaperones. Here we implicate the 
cytosolic chaperone AAA-ATPase p97/Cdc48p in ERAD. We show the association of 
mammalian p97 and its yeast homologue Cdc48p in complexes with two respective 
ERAD substrates, secretory immunoglobulin M in B lymphocytes and 6myc-Hmg2p in 
yeast. The membrane 6myc-Hmg2p as well as soluble lumenal CPY*, two short-lived 
ERAD substrates, are markedly stabilized in conditional cdc48 yeast mutants. The 
involvement of Cdc48p in dislocation is underscored by the accumulation of ERAD 
substrates in the endoplasmic reticulum when Cdc48p fails to function, as 
monitored by activation of the unfolded protein response. We propose that the 
role of p97/Cdc48p in ERAD, provided by its potential unfoldase activity and 
multiubiquitin binding capacity, is to act at the cytosolic face of the 
endoplasmic reticulum and to chaperone dislocation of ERAD substrates and 
present them to the proteasome.