The propeptide of macrophage inhibitory cytokine (MIC-1), a TGF-β superfamily member, acts as a quality control determinant for correctly folded MIC-1

被引:102
作者
Bauskin, AR [1 ]
Zhang, HP
Fairlie, WD
He, XY
Russell, PK
Moore, AG
Brown, DA
Stanley, KK
Breit, SN
机构
[1] St Vincents Hosp, Ctr Immunol, Sydney, NSW 2010, Australia
[2] Univ New S Wales, Sydney, NSW 2010, Australia
关键词
cytokine; misfolding; propeptide; proteasome; secretion;
D O I
10.1093/emboj/19.10.2212
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Macrophage inhibitory cytokine (MIC-1), a divergent member of the transforming growth facror-beta (TGF-beta) superfamily and activation associated cytokine, is secreted as a 28 kDa dimer, To understand its secretion, we examined its processing in MIC-l-transfected Chinese hamster ovary cells. Mature MIC-1 dimer arises post-endoplasmic reticulum (ER) by proteolytic cleavage of dimeric pro-MIC-l precursor at a furin-like site. Unlike previously characterized TGF-beta superfamily members, MIG-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-l precursor. There was no effect of proteasome inhibitors on cells expressing mature MIG-1 without the propeptide, suggesting that the propeptide can signal misfolding of MIG-I, 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.
引用
收藏
页码:2212 / 2220
页数:9
相关论文
共 34 条
[11]   The degradation of apolipoprotein B100 is mediated by the ubiquitin-proteasome pathway and involves heat shock protein 70 [J].
Fisher, EA ;
Zhou, MY ;
Mitchell, DM ;
Wu, XJ ;
Omura, S ;
Wang, HX ;
Goldberg, AL ;
Ginsberg, HN .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (33) :20427-20434
[12]   REQUIREMENT FOR ACTIVIN-A AND TRANSFORMING GROWTH FACTOR-BETA-1 PRO-REGIONS IN HOMODIMER ASSEMBLY [J].
GRAY, AM ;
MASON, AJ .
SCIENCE, 1990, 247 (4948) :1328-1330
[13]   ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway [J].
Hiller, MM ;
Finger, A ;
Schweiger, M ;
Wolf, DH .
SCIENCE, 1996, 273 (5282) :1725-1728
[14]   Expression and Characterization of Bone Morphogenetic Protein-2 in Chinese Hamster Ovary Cells [J].
Israel, David I. ;
Nove, John ;
Kerns, Kelvin M. ;
Moutsatsos, Ioannis K. ;
Kaufman, Randal J. .
GROWTH FACTORS, 1992, 7 (02) :139-150
[15]   THE TGF-BETA SUPERFAMILY - NEW MEMBERS, NEW RECEPTORS, AND NEW GENETIC TESTS OF FUNCTION IN DIFFERENT ORGANISMS [J].
KINGSLEY, DM .
GENES & DEVELOPMENT, 1994, 8 (02) :133-146
[16]   BREFELDIN-A - INSIGHTS INTO THE CONTROL OF MEMBRANE TRAFFIC AND ORGANELLE STRUCTURE [J].
KLAUSNER, RD ;
DONALDSON, JG ;
LIPPINCOTTSCHWARTZ, J .
JOURNAL OF CELL BIOLOGY, 1992, 116 (05) :1071-1080
[17]  
KNAPPIK A, 1994, BIOTECHNIQUES, V17, P754
[18]   ER quality control: The cytoplasmic connection [J].
Kopito, RR .
CELL, 1997, 88 (04) :427-430
[19]   Identification of a novel member of the TGF-beta superfamily highly expressed in human placenta [J].
Lawton, LN ;
Bonaldo, MD ;
Jelenc, PC ;
Qiu, L ;
Baumes, SA ;
Marcelino, RA ;
de Jesus, GM ;
Wellington, S ;
Knowles, JA ;
Warburton, D ;
Brown, S ;
Soares, MB .
GENE, 1997, 203 (01) :17-26
[20]   Degradation of 3-hydroxy-3-methylglutaryl-CoA reductase in endoplasmic reticulum membranes is accelerated as a result of increased susceptibility to proteolysis [J].
McGee, TP ;
Cheng, RH ;
Kumagai, H ;
Omura, S ;
Simoni, RD .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (41) :25630-25638