Muñoz-Estrada Jesús, Nguyen Abraham V, Goetz Sarah C
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710.
Molecular Cancer Biology Program, Duke University School of Medicine, Durham, NC 27710.
bioRxiv. 2023 Feb 1:2023.01.31.526333. doi: 10.1101/2023.01.31.526333.
Frameshift mutations in () cause spinocerebellar ataxia type 11 (SCA11), which is characterized by the progressive loss of Purkinje cells and cerebellar atrophy. Previous work showed that these variants generate truncated proteins that interfere with primary ciliary trafficking and with Sonic Hedgehog (SHH) signaling in mice. Nevertheless, the molecular mechanisms underlying the dominant interference of mutations remain unknown. Herein, we discover that SCA11-associated variants contain a peroxisomal targeting signal type 1. We find that their expression in RPE1 cells reduces peroxisome numbers within the cell and at the base of the cilia, disrupts peroxisome fission pathways, and impairs trafficking of ciliary SMO upon SHH signaling activation. This work uncovers a neomorphic function of SCA11-causing mutations and identifies requirements for both peroxisomes and cholesterol in trafficking of cilia-localized SHH signaling proteins. In addition, we postulate that molecular mechanisms underlying cellular dysfunction in SCA11 converge on the SHH signaling pathway.
（基因）中的移码突变会导致11型脊髓小脑共济失调（SCA11），其特征是浦肯野细胞进行性丧失和小脑萎缩。先前的研究表明，这些（基因）变体产生的截短蛋白会干扰小鼠的初级纤毛运输和音猬因子（SHH）信号传导。然而，突变的显性干扰背后的分子机制仍然未知。在此，我们发现与SCA11相关的变体含有1型过氧化物酶体靶向信号。我们发现它们在RPE1细胞中的表达会减少细胞内和纤毛基部的过氧化物酶体数量，破坏过氧化物酶体分裂途径，并在SHH信号激活时损害纤毛定位的SMO的运输。这项工作揭示了导致SCA11的突变的新功能，并确定了过氧化物酶体和胆固醇在纤毛定位的SHH信号蛋白运输中的需求。此外，我们推测SCA11细胞功能障碍背后的分子机制集中在SHH信号通路。
