Bardet-Biedl syndrome (BBS) is a genetic disorder that affects primary cilia. BBSome, a protein complex composed of eight BBS proteins, regulates the structure and function of cilia, and its malfunction causes BBS in humans. Here, we report a cilia-independent function of BBSome. To identify genes that regulate the C. elegans photoreceptor protein LITE-1 in ciliated ASH photosensory neurons, we performed a genetic screen and isolated bbs mutants. Functional analysis revealed that BBSome regulates LITE-1 protein stability independently of cilia. Through another round of genetic screening, we found that this cilia-independent function of BBSome is mediated by DLK-MAPK signaling, which acts downstream of BBSome to control LITE-1 stability via Rab5-mediated endocytosis. BBSome exerts its function by regulating the expression of DLK. BBSome also regulates the expression of LZK, a mammalian DLK in human cells. These studies identify a cilia-independent function of BBSome and uncover DLK as an evolutionarily conserved BBSome effector.

Bardet-Biedl 综合征 (BBS) 是一种影响初级纤毛的遗传性疾病。BBSome是一种由8个BBS蛋白组成的蛋白质复合物，调节纤毛的结构和功能，其功能障碍会导致人类的BBS。在这里，我们报告了 BBSome 的纤毛独立功能。为了鉴定调节纤毛 ASH 光感觉神经元中秀丽隐杆线虫光感受器蛋白 LITE-1 的基因，我们进行了遗传筛选并分离了bbs突变体。功能分析表明 BBSome 独立于纤毛调节 LITE-1 蛋白稳定性。通过另一轮遗传筛选，我们发现 BBSome 的这种独立于纤毛的功能是由 DLK-MAPK 信号传导介导的，该信号作用于 BBSome 下游，通过 Rab5 介导的内吞作用控制 LITE-1 的稳定性。BBSome通过调节DLK的表达来发挥其功能。BBSome 还调节人类细胞中哺乳动物 DLK LZK 的表达。这些研究确定了 BBSome 的独立于纤毛的功能，并揭示 DLK 作为进化上保守的 BBSome 效应器。