LSM12 is a Circadian Adaptor Important for ATAXIN-2-dependent Translation in Drosophila Clocks

Abstract

Mutations in human ATAXIN-2 (ATXN2/ATX2) have been implicated in neurodegenerative diseases such as spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig’s disease). Recent studies identified a RNA-binding protein complex of ATX2, TWENTY-FOUR (TYF), and polyA-binding protein (PABP) to activate translation of a rate-limiting clock gene, PERIOD (PER), in Drosophila circadian clocks. Here we demonstrate that LSM12 is a novel component of the ATX2 co-activator complex important for clock function. Lsm12 mutant flies exhibit long-period circadian behaviors with dampened PER cycling in circadian pacemaker neurons. PER overexpression rescues locomotor rhythms in Lsm12 mutants as similarly in Atx2 or tyf mutants. Moreover, Lsm12 mutation sensitizes period-lengthening effects of TYF dominant-negative, supporting that Lsm12 and tyf may share a genetic pathway for the ATX2-dependent PER translation. We validate that LSM12 associates with the ATX2-TYF protein complex in cultured Drosophila S2 cells or circadian clock neurons. More importantly, LSM12 depletion specifically blocks TYF loading onto the ATX2 co-activator and suppresses the translational activation by RNA-tethered TYF. Taken together our data suggest that LSM12 is a circadian adaptor of the ATX2 co-activator complex to stimulate TYF-mediated PER translation, thus sustaining circadian rhythms with high-amplitude PER cycling. We propose an adaptor-specific targeting of the ATX2 co-activator complex may be responsible for Atx2 effects on discrete biological time-scales such as circadian clocks or neurodegeneration.