ZMYND10 stabilizes intermediate chain proteins in the cytoplasmic pre-assembly of dynein arms

다국어 초록 (Multilingual Abstract)

<▼1><P>Zinc finger MYND-type-containing 10 (ZMYND10), a cytoplasmic protein expressed in ciliated cells, causes primary ciliary dyskinesia (PCD) when mutated; however, its function is poorly understood. Therefore, in this study, we examined the roles of ZMYND10 using <I>Zmynd10</I><SUP>–/–</SUP>mice exhibiting typical PCD phenotypes, including hydrocephalus and laterality defects. In these mutants, morphology, the number of motile cilia, and the 9+2 axoneme structure were normal; however, inner and outer dynein arms (IDA and ODA, respectively) were absent. ZMYND10 interacted with ODA components and proteins, including LRRC6, DYX1C1, and C21ORF59, implicated in the cytoplasmic pre-assembly of DAs, whose levels were significantly reduced in <I>Zmynd10</I><SUP>–/–</SUP>mice. LRRC6 and DNAI1 were more stable when co-expressed with ZYMND10 than when expressed alone. DNAI2, which did not interact with ZMYND10, was not stabilized by co-expression with ZMYND10 alone, but was stabilized by co-expression with DNAI1 and ZMYND10, suggesting that ZMYND10 stabilized DNAI1, which subsequently stabilized DNAI2. Together, these results demonstrated that ZMYND10 regulated the early stage of DA cytoplasmic pre-assembly by stabilizing DNAI1.</P></▼1><▼2><P><B>Author summary</B></P><P>Dynein arm defects are linked to primary ciliary dyskinesia (PCD). ZMYND10 increased the stability of its interacting proteins and specifically regulated intermediate chain protein assembly, revealing tightly regulated mechanisms underlying dynein arm assembly and PCD-related pathogenesis. Increasing protein stability could be useful for developing PCD therapeutics.</P></▼2>