Hsp70 incompletely disaggregates the misfolding K488X-menin, promoting the tumorigenesis in a multiple endocrine neoplasia type 1 family

Abstract

Previous standpoints involved into the nonsense mutations and missense variants which caused truncated inactive menin protein of Multiple Endocrine Neoplasia Type 1(MEN1) gene, including loss of heterozygosity(LOH) and menin mutants degradation, cannot wholly interpret MEN1 pathogenesis. A c.1462A > T (p.K488X) mutation in exon10 of MEN1 was identified as the potential pathogenic mutation in an extended Chinese MEN1 family in this study. Ubiquitination modification degradation of K488X-menin result from the combined actions of carboxy-terminus of Hsc70-interacting protein (CHIP) and Hsp70 in vitro. K488X‒menin is a misfolding truncated protein that results in amyloid aggregation state in live cells or the affected tissues, the aggregation of which is promoted by Hsp70 and CHIP. Although Hsp70 disaggregate the aggregated of K488X-menin in vitro, the Hsp70 which is not upregulated in the MEN1 patients’ affected tissue can not completely disaggregate the aggregated K488X, which becomes a toxic intermediate to trigger development process of early tumorigenesis verified in the mutant zebrafish model and the affected tissues to cause the tumorigenic phenotypes in this MEN1 case. Our findings provide a complete novel interpretation to the mechanism of MEN1 tumorigenesis.