신희권 (Columbia University Irving Medical Center) | 한빛사논문 > 한빛사

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신희권Heegwon Shin

Columbia University Irving Medical Center

Sci. Immunol., Oct 27 2023, 8 (88) | https://doi.org/10.1126/sciimmunol.adg2979 Long 3'UTRs predispose neurons to inflammation by promoting immunostimulatory double-stranded RNA formation

Tyler J Dorrity ^{1 †}, Heegwon Shin ^{1 †}, Kenenni A Wiegand ¹, Justin Aruda ¹, Michael Closser ^{2 3 4}, Emily Jung ¹, Jake A Gertie ^{1 5 6}, Amanda Leone ¹, Rachel Polfer ¹, Bruce Culbertson ^{5 6}, Lisa Yu ¹, Christine Wu ¹, Takamasa Ito ¹, Yuefeng Huang ¹, Anna-Lena Steckelberg ⁷, Hynek Wichterle ^{2 3 4}, Hachung Chung ^{1 *}

¹Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.
²Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
³Department of Neuroscience and Neurology, Columbia University Irving Medical Center, New York, NY, USA.
⁴Center for Motor Neuron Biology and Disease, Columbia University Irving Medical Center, New York, NY, USA.
⁵Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
⁶Medical Scientist Training Program, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
⁷Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.

^†These authors contributed equally
^*Corresponding author: correspondence to Hachung Chung

Abstract

Loss of RNA homeostasis underlies numerous neurodegenerative and neuroinflammatory diseases. However, the molecular mechanisms that trigger neuroinflammation are poorly understood. Viral double-stranded RNA (dsRNA) triggers innate immune responses when sensed by host pattern recognition receptors (PRRs) present in all cell types. Here, we report that human neurons intrinsically carry exceptionally high levels of immunostimulatory dsRNAs and identify long 3'UTRs as giving rise to neuronal dsRNA structures. We found that the neuron-enriched ELAVL family of genes (ELAVL2, ELAVL3, and ELAVL4) can increase (i) 3'UTR length, (ii) dsRNA load, and (iii) activation of dsRNA-sensing PRRs such as MDA5, PKR, and TLR3. In wild-type neurons, neuronal dsRNAs signaled through PRRs to induce tonic production of the antiviral type I interferon. Depleting ELAVL2 in WT neurons led to global shortening of 3'UTR length, reduced immunostimulatory dsRNA levels, and rendered WT neurons susceptible to herpes simplex virus and Zika virus infection. Neurons deficient in ADAR1, a dsRNA-editing enzyme mutated in the neuroinflammatory disorder Aicardi-Goutières syndrome, exhibited intolerably high levels of dsRNA that triggered PRR-mediated toxic inflammation and neuronal death. Depleting ELAVL2 in ADAR1 knockout neurons led to prolonged neuron survival by reducing immunostimulatory dsRNA levels. In summary, neurons are specialized cells where PRRs constantly sense "self" dsRNAs to preemptively induce protective antiviral immunity, but maintaining RNA homeostasis is paramount to prevent pathological neuroinflammation.

논문정보

형식Research article
게재일2023년 10월 (BRIC 등록일 2023-11-03)
연구진국외 연구진
분야 생명과학 > 면역학

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