Structural insights into RNase J that plays an essential role in Mycobacterium tuberculosis RNA metabolism

Abstract

Ribonucleases (RNases) are responsible for RNA metabolism. RNase J, the core enzyme of the RNA degradosome, plays an essential role in global mRNA decay. Emerging evidence showed that the RNase J of Mycobacterium tuberculosis (Mtb-RNase J) could be an excellent target for treating Mtb infection. Here, crystal structures of Mtb-RNase J in apo-state and complex with the single-strand RNA reveal the conformational change upon RNA binding and hydrolysis. Mtb-RNase J forms an active homodimer through the interactions between the β-CASP and the β-lactamase domain. Knockout of RNase J slows the growth rate and changes the colony morphologies and cell length in Mycobacterium smegmatis, which is restored by RNase J complementation. Finally, RNA-seq analysis shows that the knockout strain significantly changes the expression levels of 49 genes in metabolic pathways. Thus, our current study explores the structural basis of Mtb-RNase J and might provide a promising candidate in pharmacological treatment for tuberculosis.

New option: targeting RNase J and RNase HI in the fight against multi-drug-resistant tuberculosis

“…Antibiotic resistance in MTB was previously linked to mutations in RNase J, a bacterial enzyme involved in the processing and degradation of RNA. Bao et al 17 observed growth rate, colony morphologies, aggregation and motility of Mycobacterium smegmatis were dramatically slowed down by RNase J knockdown, and this was reversed when the RNase J gene was supplemented. The loss of RNase J can lead to drug tolerance, which is beneficial for managing drug stress during tuberculosis therapy but may also lead to high-level drug resistance in clinical settings 18 .…”

The Structural and Molecular Mechanisms of Mycobacterium tuberculosis Translational Elongation Factor Proteins

“…The structures of several key proteins of Mtb have been elucidated, e.g., membrane transporter MmpL3 [82,83], RNase J [84], fatty acyl-AMP ligase FadD32 [85], acetyltransferase Eis [86], EF-Tu/EF-Ts [49], EF-G [68], and nucleoside triphosphate pyrophosphohydrolase MazG [87]. Inhibitors of these proteins are considered promising for the treatment of tuberculosis, among which 11 potential anti-tuberculosis drugs have been obtained by Li et al, based on the rational drug of acetyltransferase Eis [86].…”

Harnessing the potential of lipid nanoparticles for the delivery of chemically modified siRNA to combat hepatic adenovirus infection

“… 5 However, their clinical application faces significant challenges due to rapid enzymatic degradation of RNA, primarily catalyzed by ribonucleases. 6 RNA instability arises from the susceptibility of ribose sugar’s 2′-OH group to base-catalyzed hydrolysis, leading to phosphodiester bond degradation. To address this, Geisler et al.…”