Article

Meckel-Gruber syndrome protein MKS3 is required for endoplasmic reticulum-associated degradation of surfactant protein C.

Division of Pulmonary Biology, Cincinnati Children's Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA.
Journal of Biological Chemistry (impact factor: 4.77). 10/2009; 284(48):33377-83. DOI:10.1074/jbc.M109.034371
Source: PubMed

ABSTRACT Autosomal dominant mutations in the SFTPC gene are associated with idiopathic pulmonary fibrosis, a progressive lethal interstitial lung disease. Mutations that cause misfolding of the encoded proprotein surfactant protein C (SP-C) trigger endoplasmic reticulum (ER)-associated degradation, a pathway that segregates terminally misfolded substrate for retrotranslocation to the cytosol and degradation by proteasome. Microarray screens for genes involved in SP-C ER-associated degradation identified MKS3/TMEM67, a locus previously linked to the ciliopathy Meckel-Gruber syndrome. In this study, MKS3 was identified as a membrane glycoprotein predominantly localized to the ER. Expression of MKS3 was up-regulated by genetic or pharmacological inducers of ER stress. The ER lumenal domain of MKS3 interacted with a complex that included mutant SP-C and associated chaperones, whereas the region predicted to encode the transmembrane domains of MKS3 interacted with cytosolic p97. Deletion of the transmembrane and cytosolic domains abrogated interaction of MKS3 with p97 and resulted in accumulation of mutant SP-C proprotein; knockdown of MKS3 also inhibited degradation of mutant SP-C. These results support a model in which MKS3 links the ER lumenal quality control machinery with the cytosolic degradation apparatus.

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Keywords

Autosomal dominant mutations
 
cause misfolding
 
ciliopathy Meckel-Gruber syndrome
 
cytosolic degradation apparatus
 
cytosolic p97
 
encoded proprotein surfactant protein C
 
endoplasmic reticulum
 
idiopathic pulmonary fibrosis
 
included mutant SP-C
 
membrane glycoprotein
 
Microarray screens
 
mutant SP-C
 
mutant SP-C proprotein
 
progressive lethal interstitial lung disease
 
results support
 
segregates terminally misfolded substrate
 
SFTPC gene
 
SP-C ER-associated degradation
 
transmembrane
 
transmembrane domains