Sharma Rahul, Wu Kaiyuan, Han Kim, Russo Anna Chiara, Dagur Pradeep K, Combs Christian A, Sack Michael N
Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Maryland, USA.
Cardiovascular Branch, NHLBI, NIH, Maryland, USA.
bioRxiv. 2024 Mar 27:2024.03.21.586144. doi: 10.1101/2024.03.21.586144.
The levels of biogenesis of lysosome organelles complex 1 subunit 1 (BLOC1S1) control mitochondrial and endolysosome organelle homeostasis and function. Reduced fidelity of these vacuolar organelles is increasingly being recognized as important in instigating cell-autonomous immune cell activation. We reasoned that exploring the role of BLOC1S1 in CD4 T cells, may further advance our understanding of regulatory events linked to mitochondrial and/or endolysosomal function in adaptive immunity. Transcript levels of the canonical transcription factors driving CD4T cell polarization in response to activation showed that, the T2 regulator GATA3 and phosphorylated STAT6 were preferentially induced in BLOC1S1 depleted primary CD4 T (TKO) cells. In parallel, in response to both T cell receptor activation and in response to TH2 polarization the levels of IL-4, IL-5 and IL-13 were markedly induced in the absence of BLOC1S1. At the organelle level, mitochondrial DNA leakage evoked cGAS-STING and NF-kB pathway activation with subsequent T2 polarization. The induction of autophagy with rapamycin reduced cytosolic mtDNA and reverses these T2 signatures. Furthermore, genetic knockdown of STING and STING and NF-κB inhibition ameliorated this immune regulatory cascade in TKO cells. Finally, at a functional level, TKO mice displayed increased susceptible to allergic conditions including atopic dermatitis and allergic asthma. In conclusion, BLOC1S1 depletion mediated disruption of mitochondrial integrity to initiate a predominant TH2 responsive phenotype via STING-NF-κB driven signaling of the canonical T2 regulatory program.
溶酶体细胞器复合物1亚基1(BLOC1S1)的生物合成水平控制线粒体和内溶酶体细胞器的稳态及功能。这些液泡细胞器保真度的降低日益被认为在引发细胞自主免疫细胞激活中起重要作用。我们推断,探索BLOC1S1在CD4 T细胞中的作用,可能会进一步推进我们对适应性免疫中与线粒体和/或内溶酶体功能相关的调节事件的理解。驱动CD4 T细胞在激活后极化的典型转录因子的转录水平表明,在BLOC1S1缺失的原代CD4 T(TKO)细胞中,T2调节因子GATA3和磷酸化的STAT6被优先诱导。同时,在没有BLOC1S1的情况下,响应T细胞受体激活和TH2极化,IL-4、IL-5和IL-13的水平均显著升高。在细胞器水平上,线粒体DNA泄漏引发cGAS-STING和NF-κB途径激活,随后导致T2极化。用雷帕霉素诱导自噬可减少细胞质中的线粒体DNA并逆转这些T2特征。此外,STING基因敲低以及STING和NF-κB抑制改善了TKO细胞中的这种免疫调节级联反应。最后,在功能水平上,TKO小鼠对包括特应性皮炎和过敏性哮喘在内的过敏性疾病表现出更高的易感性。总之,BLOC1S1缺失介导线粒体完整性破坏,通过STING-NF-κB驱动的经典T2调节程序信号传导引发主要的TH2反应性表型。