Chaperone interactions of the metalloproteinase meprin A in the secretory or proteasomal-degradative pathway

The secreted form of mouse meprin A is a homooligomer of meprin α subunits that contain a prosequence, a catalytic domain, and three domains designated as MAM (meprin, A5 protein, receptor protein-tyrosine phosphatase μ), MATH (meprin and TRAF homology), and AM (AfterMath). Previous studies in dicated that wild-type mouse meprin α is predominantly a secreted protein, while the MAM deletion mutant (ΔMAM) is degraded intracellularly. The work herein indicates that the ΔMAM mutant is ubiquitinated and degraded via the proteasomal pathway. Both wild-type meprin α and the ΔMAM mutant interact with the molecular chaperones calnexin and calreticulin in the endoplasmic reticulum. The interactions of the chaperones with the ΔMAM mutant were significantly prolonged in the presence of lactacystin, a specific inhibitor of the proteasome, whereas those with the wild type were not affected by this inhibitor. Trimming of the Asn-linked core oligosaccharides of meprin subunits was required for interactions with the chaperones. The data indicated that folding of the wild-type protein was accelerated by chaperones, whereas the rate of dimerization was unaffected. Thus, calnexin and calreticulin are intimately involved in the correct folding and transport of meprin to the plasma membrane, as well as in retrograde transport of the ΔMAM mutant to the ubiquitin-dependent proteasomal degradative pathway in the cytosol.