HnRNPQ suppresses polyglutamineaggregation by post-transcriptional regulation of vaccinia-related kinase 2

Abstract

Themisfoldingofproteinswithabnormallypolyglutamine(polyQ)expansioncauseneurodegenerativedisordersincludingHuntington'sdisease(HD).TCP-1ringcomplex(TRiC)/Chaperonin-containing TCP-1(CCT)hasanessentialroleinprotectingagainsttheaggregationandcytotoxicityofpolyQproteins.Notably,wehavepreviouslyshownthatvaccinia-relatedkinase2(VRK2)downregulateschaperoninTRiCproteinlevelsthroughtheubiquitin-proteasomesystembydestabilizingubiquitin-specificprotease25(USP25). VRK2expressionisknowntobemuchhigherinactivelyproliferatingcells,butismaintainedatalowlevelinthebrainbecauseitmakescellspronetopolyQaggregation.Herewefoundthatneuronalcell-specificbasallevelofVRK2isregulatednotbytranscriptionalregulationbutbypost-transcriptionalregulation. HnRNPQspecificallybindsto3’UTRofVrk2mRNAinneuronalcellsandreduceditsmRNAstability.WereportadramaticdecreaseinCCT4levelbyreducinghnRNPQ,whichcontributetoincreaseinpolyQaggregation.Thus,ourresultsdemonstratethatthelevelofbrainhnRNPQcontributestoHDprogressionbyregulatingVrk2mRNAstabilityandopennewnobleprognosticmarkerofHD.2