Department of Medicine, University of Calgary, Calgary, Canada.
Snyder Institute for Chronic Disease, University of Calgary, Calgary, Canada.
Life Sci Alliance. 2020 Dec 29;4(3). doi: 10.26508/lsa.202000897. Print 2021 Mar.
The pryin domain (PYD) domain is involved in protein interactions that lead to assembly of immune-sensing complexes such as inflammasomes. The repertoire of PYD-containing genes expressed by a cell type arms tissues with responses against a range of stimuli. The transcriptional regulation of the PYD gene family however is incompletely understood. Alternative promoter utilization was identified as a mechanism regulating the tissue distribution of human PYD gene family members, including NLRP6 that is translationally silenced outside of intestinal tissue. Results show that alternative transcriptional promoters mediate NLRP6 silencing in mice and humans, despite no upstream genomic synteny. Human NLRP6 contains an internal alternative promoter within exon 2 of the PYD, resulting in a truncated mRNA in nonintestinal tissue. In mice, a proximal promoter was used that expanded the 5' leader sequence restricting nuclear export and abolishing translational efficiency. Nlrp6 was dispensable in disease models targeting the kidney, which expresses noncanonical isoforms. Thus, alternative promoter use is a critical mechanism not just for isoform modulation but for determining expression profile and function of PYD family members.
PYD 结构域参与蛋白相互作用，导致免疫感应复合物（如炎症小体）的组装。细胞类型表达的含有 PYD 结构域的基因库为组织提供了针对一系列刺激的反应。然而，PYD 基因家族的转录调控机制尚不完全清楚。替代启动子的利用被确定为调节人类 PYD 基因家族成员组织分布的一种机制，包括 NLRP6，其在肠外组织中被翻译沉默。结果表明，尽管没有上游基因组同线性，但替代转录启动子介导了小鼠和人类 NLRP6 的沉默。人类 NLRP6 在 PYD 的外显子 2 内含有一个内部替代启动子，导致在非肠组织中产生截断的 mRNA。在小鼠中，使用了一个近端启动子，该启动子扩展了 5' 前导序列，限制了核输出并消除了翻译效率。在针对肾脏的疾病模型中，Nlrp6 是可有可无的，因为肾脏表达非典型同工型。因此，替代启动子的使用不仅是调节同工型的关键机制，也是决定 PYD 家族成员表达谱和功能的关键机制。
