Lau Laura, Cariaga Taryn A, Chang Abraham B, Lane Joan H, Purtha Whitney E, Rapaport Aaron S, Hu Ruozhen, Konno Hiroyasu, Bulloch Daryl N, Rardin Matthew J, Gibson Bradford W, Devoss Jason, Ouyang Wenjun, Manzanillo Paolo S
Amgen Research, Amgen Inc., 720 Gateway Blvd, South San Francisco, CA, 94080, USA.
Gilead Inc, 333 Lakeside Dr, Foster City, CA, 94404, USA.
Nat Commun. 2025 Jan 24;16(1):968. doi: 10.1038/s41467-024-55690-0.
TASL is an immune adaptor that binds to the solute carrier SLC15A4 and facilitates activation of the transcription factor IRF5 during Toll-like receptor (TLR) signaling. Similar to IRF5 and SLC15A4, single nucleotide polymorphisms (SNPs) within TASL have been implicated in increased susceptibility to systemic lupus erythematosus (SLE) in patients. However, the biological function of TASL in vivo and how SLE-associated SNPs increase disease risk is unknown. Here we report that mice deficient in Tasl lack responses to TLR7/9 stimulation and are protected from autoimmune symptoms induced by Aldara or pristane. Loss of Tasl reduces IRF5 phosphorylation and cytokine production in multiple immune cell types but has no effect on other aspects of TLR signaling. Conversely, an SLE-associated TASL risk variant increases TASL protein expression via codon usage, resulting in augmented cytokine production in human cells. Altogether, our study validates the essential function of TASL in TLR signaling and autoimmune pathogenesis.
TASL是一种免疫衔接蛋白，可与溶质载体SLC15A4结合，并在Toll样受体（TLR）信号传导过程中促进转录因子IRF5的激活。与IRF5和SLC15A4类似，TASL内的单核苷酸多态性（SNP）与患者系统性红斑狼疮（SLE）易感性增加有关。然而，TASL在体内的生物学功能以及SLE相关SNP如何增加疾病风险尚不清楚。在此我们报告，缺乏Tasl的小鼠对TLR7/9刺激无反应，并免受咪喹莫特或 pristane诱导的自身免疫症状影响。Tasl的缺失降低了多种免疫细胞类型中IRF5的磷酸化和细胞因子产生，但对TLR信号传导的其他方面没有影响。相反，一种SLE相关的TASL风险变体通过密码子使用增加TASL蛋白表达，导致人类细胞中细胞因子产生增加。总之，我们的研究验证了TASL在TLR信号传导和自身免疫发病机制中的重要功能。
