The Mrj co-chaperone mediates keratin turnover and prevents the formation of toxic inclusion bodies in trophoblast cells of the placenta.
Defects in protein-folding and -degradation machinery have been identified as a major cause of intracellular protein aggregation and of aggregation-associated diseases. In general, it remains unclear how these aggregates are harmful to normal cellular function. We demonstrate here that, in the developing placenta of the mouse, the absence of the Mrj (Dnajb6) co-chaperone prevents proteasome degradation of keratin 18 (K18; Krt18) intermediate filaments, resulting in the formation of keratin inclusion bodies. These inclusions in chorionic trophoblast cells prevent chorioallantoic attachment during placental development. We show further that keratin-deficient embryos undergo chorioallantoic attachment and that, by genetically reducing keratin expression in Mrj(-/-) conceptuses, chorioallantoic attachment was rescued. Therefore, the chorioallantoic attachment phenotype in Mrj mutants is not due to a deficiency of the normal keratin cytoskeleton, but rather is cytotoxicity caused by keratin aggregates that disrupt chorion trophoblast cell organization and function.
Watson
Erica D
ED
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
Geary-Joo
Colleen
C
Hughes
Martha
M
Cross
James C
JC
D000482:Allantois / Q000002:abnormalities; D000818:Animals; D002823:Chorion / Q000002:abnormalities; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006470:Hemorrhage; D002479:Inclusion Bodies / Q000378:metabolism*; D007633:Keratins / Q000378:metabolism*; D008297:Male; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*
C118476:Dnajb6 protein, mouse; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D007633:Keratins; D046988:Proteasome Endopeptidase Complex