COVID-19-activated SREBP2 disturbs cholesterol biosynthesis and leads to cytokine storm

被引:103
作者
Lee, Wonhwa [1 ]
Ahn, June Hong [2 ,3 ]
Park, Hee Ho [4 ]
Kim, Hong Nam [5 ,6 ]
Kim, Hyelim [7 ]
Yoo, Youngbum [1 ]
Shin, Hyosoo [1 ,7 ]
Hong, Kyung Soo [8 ]
Jang, Jong Geol [8 ]
Park, Chun Gwon [8 ,9 ]
Choi, Eun Young [2 ,3 ]
Bae, Jong-Sup [10 ]
Seo, Young-Kyo [1 ]
机构
[1] Korea Res Inst Biosci & Biotechnol, Aging Res Ctr, Daejeon 34141, South Korea
[2] Yeungnam Univ, Coll Med, Dept Internal Med, Div Pulmonol & Allergy, Daegu 42415, South Korea
[3] Yeungnam Univ, Reg Ctr Resp Dis, Med Ctr, Daegu 42415, South Korea
[4] Kangwon Natl Univ, Dept Biotechnol & Bioengn, Chunchon 24341, Gangwon Do, South Korea
[5] Korea Inst Sci & Technol KIST, Brain Sci Inst, Ctr BioMicrosyst, Seoul 02792, South Korea
[6] Korea Univ Sci & Technol, KIST Sch, Div Biomed Sci & Technol, Seoul 02792, South Korea
[7] Chungnam Natl Univ, Coll Pharm, Daejeon 34134, South Korea
[8] Sungkyunkwan Univ SKKU, SKKU Inst Convergence, Dept Biomed Engn, Suwon, South Korea
[9] Sungkyunkwan Univ, Biomed Inst Convergence, SKKU BICS, 2066 Seobu Ro, Suwon 16419, South Korea
[10] Kyungpook Natl Univ, Res Inst Pharmaceut Sci, BK21 Plus KNU Multi Based Creat Drug Res Team, Coll Pharm,CMRI, Daegu 41566, South Korea
基金
新加坡国家研究基金会;
关键词
COVID-19; TRANSCRIPTION; SUPPRESSES; METABOLISM; PATHWAYS; BINDING; PROTEIN; SEPSIS; MTORC1; GENES;
D O I
10.1038/s41392-020-00292-7
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients' blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-kappa B suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.
引用
收藏
页数:11
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