A Possible Role of ER-60 Protease in the Degradation of Misfolded Proteins in the Endoplasmic Reticulum

Abstract

Wild-type human lysozyme (hLZM) is secreted when expressed in mouse L cells, whereas misfolded mutant hLZMs are retained and eventually degraded in a pre-Golgi compartment (Omura, F., Otsu, M., Yoshimori, T., Tashiro, Y., and Kikuchi, M. (1992) Eur. J. Biochem. 210, 591-599). These misfolded mutant hLZMs are associated with protein disulfide isomerase (Otsu, M., Omura, F., Yoshimori, T., and Kikuchi, M. (1994) J. Biol. Chem. 269, 6874-6877). From the observation that this degradation is sensitive to cysteine protease inhibitors, such as N-acetyl-leucyl-leucyl-norleucinal and N-acetyl-leucyl-leucyl-methioninal, but not to the serine protease inhibitors, 1-chloro-3-tosylamido-7-amino-2-heptanone and (p-amidinophenyl)methanesulfonyl fluoride, it was suggested that some cysteine proteases are likely responsible for the degradation of abnormal proteins in the endoplasmic reticulum (ER). ER-60 protease (ER-60), an ER resident protein with cysteine protease activity (Urade, R., Nasu, M., Moriyama, T., Wada, K., and Kito, M. (1992) J. Biol. Chem. 267, 15152-15159), was found to associate with misfolded hLZMs, but not with the wild-type protein, in mouse L cells. Furthermore, denatured hLZM is degraded by ER-60 in vitro, whereas native hLZM is not. These results suggest that ER-60 could be a component of the proteolytic machinery for the degradation of misfolded mutant hLZMs in the ER.

Selective Degradation of Accumulated Secretory Proteins in the Endoplasmic Reticulum

“…Recently, ER-60 protease, an ER-resident protein with cysteine protease activity (53,54), has been characterized and related to ER degradation in vivo for the first time by its association with misfolded human lysozyme prior to its degradation (52). In addition to ER-60, a second protease, termed ER-72 protease, has also been identified in the ER and is inhibited by cysteine protease inhibitors (55).…”

The protein disulphide-isomerase family: unravelling a string of folds

“…ERp57 exhibits a lower redox activity than PDI, as seen in a glutathione-insulin transhydrogenase assay [150,151], and cannot substitute for PDI in P4H [116]. Although ERp57 has been claimed to possess carnitine medium\long-chain acyltransferase (CPT) activity [152,153] and proteolytic activity [137,154,155] dependent on its active-site cysteines [156], both of these claims have been challenged [157].…”

Association of ERp57 with Mouse MHC Class I Molecules Is Tapasin Dependent and Mimics That of Calreticulin and not Calnexin

“…ERp57 has thiol-dependent reductase activity (29), cysteine-dependent protease activity (30,31), and is known to interact with glycoproteins in a manner that can involve forming complexes with either CXN and CRT (32)(33)(34). Three recent reports demonstrated that ERp57 is detected in association with class I molecules before peptide binding (26 -28).…”