Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Cell Rep. 2024 Mar 26;43(3):113886. doi: 10.1016/j.celrep.2024.113886. Epub 2024 Mar 1.
The human WDR33 gene encodes three major isoforms. The canonical isoform WDR33v1 (V1) is a well-characterized nuclear mRNA polyadenylation factor, while the other two, WDR33v2 (V2) and WDR33v3 (V3), have not been studied. Here, we report that V2 and V3 are generated by alternative polyadenylation, and neither protein contains all seven WD (tryptophan-aspartic acid) repeats that characterize V1. Surprisingly, V2 and V3 are not polyadenylation factors but localize to the endoplasmic reticulum and interact with stimulator of interferon genes (STING), the immune factor that induces the cellular response to cytosolic double-stranded DNA. V2 suppresses interferon-β induction by preventing STING disulfide oligomerization but promotes autophagy, likely by recruiting WIPI2 isoforms. V3, on the other hand, functions to increase STING protein levels. Our study has not only provided mechanistic insights into STING regulation but also revealed that protein isoforms can be functionally completely unrelated, indicating that alternative mRNA processing is a more powerful mechanism than previously appreciated.
人类 WDR33 基因编码三种主要的异构体。经典的异构体 WDR33v1（V1）是一种经过充分研究的核 mRNA 多聚腺苷酸化因子，而另外两种异构体 WDR33v2（V2）和 WDR33v3（V3）尚未被研究。在这里，我们报告 V2 和 V3 是通过可变多聚腺苷酸化产生的，并且这两种蛋白质都不包含表征 V1 的所有七个 WD（色氨酸-天冬氨酸）重复序列。令人惊讶的是，V2 和 V3 不是多聚腺苷酸化因子，而是定位于内质网并与干扰素基因刺激物（STING）相互作用，STING 是诱导细胞对细胞溶质双链 DNA 反应的免疫因子。V2 通过防止 STING 二硫键寡聚化来抑制干扰素-β的诱导，但促进自噬，可能通过招募 WIPI2 异构体。另一方面，V3 的功能是增加 STING 蛋白水平。我们的研究不仅为 STING 调节提供了机制上的见解，还揭示了蛋白质异构体在功能上可能完全无关，这表明可变 mRNA 加工是一种比以前认识到的更强大的机制。
