Premium
The propeptide of macrophage inhibitory cytokine (MIC‐1), a TGF‐β superfamily member, acts as a quality control determinant for correctly folded MIC‐1
Author(s) -
Bauskin Asne R.,
Zhang HongPing,
Fairlie W.Douglas,
He Xiao Yan,
Russell Patricia K.,
Moore Anthony G.,
Brown David A.,
Stanley Keith K.,
Breit Samuel N.
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.10.2212
Subject(s) - protein precursor , biology , endoplasmic reticulum , brefeldin a , furin , signal peptide , secretion , proteasome , secretory protein , biochemistry , microbiology and biotechnology , peptide sequence , golgi apparatus , gene , enzyme
Macrophage inhibitory cytokine (MIC‐1), a divergent member of the transforming growth factor‐β (TGF‐β) superfamily and activation associated cytokine, is secreted as a 28 kDa dimer. To understand its secretion, we examined its processing in MIC‐1‐transfected Chinese hamster ovary cells. Mature MIC‐1 dimer arises post‐endoplasmic reticulum (ER) by proteolytic cleavage of dimeric pro‐MIC‐1 precursor at a furin‐like site. Unlike previously characterized TGF‐β superfamily members, MIC‐1 dimers are also secreted in constructs lacking the propeptide. A clue to the function of the propeptide came from the observation that a range of proteasome inhibitors, including lactacystin and MG132, cause major increases in levels of undimerized pro‐MIC‐1 precursor. There was no effect of proteasome inhibitors on cells expressing mature MIC‐1 without the propeptide, suggesting that the propeptide can signal misfolding of MIC‐1, leading to proteasomal degradation. Deletion mutagenesis showed the N‐terminal 28 amino acids of the propeptide are necessary for proteasomal degradation. This is the first demonstration, to our knowledge, of a quality control function in a propeptide domain of a secretory protein and represents an additional mechanism to ensure correct folding of proteins leaving the ER.