THE ROLE OF REGULATED RNA DECAY BY RNASE L IN HOMEOSTASIS AND INNATE IMMUNITY

Abstract

Mammalian cells are equipped with mechanisms to fight infections directly and rapidly before adaptive immunity can be invoked. Activation of these immediate mechanisms is called the innate immune response and universally involves induction of interferons and inflammatory cytokines. When innate immunity is triggered by immunogenic double-stranded RNA (dsRNA), the cells additionally start cleaving their own RNAs due to activation of an unusual receptor kinase-endoribonuclease, RNase L. We combine X-ray crystallography, biochemistry, cell biology and RNA-seq to decipher the function of RNase L-induced RNA decay in dsRNA response. Our work identified the first direct cellular RNA targets of human RNase L. From this work RNase L emerges as a sharp, yet tunable, instrument of the innate immune system. Under homeostasis, this instrument controls the levels of select mRNAs to inhibit proliferation and metastasis, resembling the action of tumor-suppressing microRNAs such as miR-200. On the other hand, under acute dsRNA stress, RNase L rapidly blocks global translation and creates a privileged landscape for interferon synthesis. This work illuminates how RNase L is repurposed for distinct functions from homeostasis to innate immune response based on dsRNA load.