PMID- 10811612
OWN - NLM
STAT- MEDLINE
DCOM- 20000622
LR  - 20181113
IS  - 0261-4189 (Print)
IS  - 1460-2075 (Electronic)
IS  - 0261-4189 (Linking)
VI  - 19
IP  - 10
DP  - 2000 May 15
TI  - The propeptide of macrophage inhibitory cytokine (MIC-1), a TGF-beta superfamily 
      member, acts as a quality control determinant for correctly folded MIC-1.
PG  - 2212-20
AB  - Macrophage inhibitory cytokine (MIC-1), a divergent member of the transforming 
      growth factor-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-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-beta 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.
FAU - Bauskin, A R
AU  - Bauskin AR
AD  - Centre for Immunology, St Vincent's Hospital and University of New South Wales, 
      Sydney, NSW 2010, Australia. a.bauskin@cfi.unsw.edu.au
FAU - Zhang, H P
AU  - Zhang HP
FAU - Fairlie, W D
AU  - Fairlie WD
FAU - He, X Y
AU  - He XY
FAU - Russell, P K
AU  - Russell PK
FAU - Moore, A G
AU  - Moore AG
FAU - Brown, D A
AU  - Brown DA
FAU - Stanley, K K
AU  - Stanley KK
FAU - Breit, S N
AU  - Breit SN
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Cytokines)
RN  - 0 (Growth Differentiation Factor 15)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Transforming Growth Factor beta)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Animals
MH  - CHO Cells
MH  - Cricetinae
MH  - Cysteine Endopeptidases/chemistry/metabolism
MH  - Cytokines/*chemistry/metabolism
MH  - Glycosylation
MH  - Growth Differentiation Factor 15
MH  - Multienzyme Complexes/chemistry/metabolism
MH  - Proteasome Endopeptidase Complex
MH  - *Protein Folding
MH  - Transforming Growth Factor beta/*chemistry/metabolism
PMC - PMC384362
EDAT- 2000/05/16 09:00
MHDA- 2000/07/06 11:00
PMCR- 2001/05/15
CRDT- 2000/05/16 09:00
PHST- 2000/05/16 09:00 [pubmed]
PHST- 2000/07/06 11:00 [medline]
PHST- 2000/05/16 09:00 [entrez]
PHST- 2001/05/15 00:00 [pmc-release]
AID - cdd225 [pii]
AID - 10.1093/emboj/19.10.2212 [doi]
PST - ppublish
SO  - EMBO J. 2000 May 15;19(10):2212-20. doi: 10.1093/emboj/19.10.2212.