To kill a microRNA: emerging concepts in target-directed microRNA degradation
Amber F Buhagiar1, Benjamin Kleaveland1
1Department of Pathology and Lab Medicine, Weill Cornell Medicine, New York, NY10065, USA.
Abstract:
MicroRNAs (miRNAs) guide Argonaute (AGO) proteins to bind mRNA targets. Although most targets are destabilized by miRNA-AGO binding, some targets induce degradation of the miRNA instead. These special targets are also referred to as trigger RNAs. All triggers identified thus far have binding sites with greater complementarity to the miRNA than typical target sites. Target-directed miRNA degradation (TDMD) occurs when trigger RNAs bind the miRNA-AGO complex and recruit the ZSWIM8 E3 ubiquitin ligase, leading to AGO ubiquitination and proteolysis and subsequent miRNA destruction. More than 100 different miRNAs are regulated by ZSWIM8 in bilaterian animals, and hundreds of trigger RNAs have been predicted computationally. Disruption of individual trigger RNAs or ZSWIM8 has uncovered important developmental and physiologic roles for TDMD across a variety of model organisms and cell types. In this review, we highlight recent progress in understanding the mechanistic basis and functions of TDMD, describe common features of trigger RNAs, outline best practices for validating trigger RNAs, and discuss outstanding questions in the field.
Insights
Trigger RNAs degrade microRNAs (miRNAs) through target-directed miRNA degradation (TDMD). This process involves ZSWIM8 E3 ubiquitin ligase and is crucial for regulating gene expression in animals.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- MicroRNAs (miRNAs) regulate gene expression by binding mRNA targets via Argonaute (AGO) proteins.
- While most miRNA-AGO interactions destabilize mRNA, some trigger RNAs degrade the miRNA itself.
- Trigger RNAs exhibit higher complementarity to miRNAs than typical miRNA targets.
Approach:
- This review synthesizes recent findings on the mechanism and function of Target-Directed miRNA Degradation (TDMD).
- It details the role of ZSWIM8 E3 ubiquitin ligase in recruiting the degradation machinery.
- The review outlines common characteristics of trigger RNAs and validation methodologies.
Key Points:
- Target-directed miRNA degradation (TDMD) is a regulatory pathway where specific trigger RNAs lead to miRNA destruction.
- ZSWIM8 E3 ubiquitin ligase is central to TDMD, mediating AGO protein ubiquitination and proteolysis.
- Hundreds of trigger RNAs and over 100 miRNAs are regulated by ZSWIM8 in bilaterian animals.
Conclusions:
- TDMD plays significant roles in development and physiology across diverse organisms.
- Understanding trigger RNA features and validation is key to advancing TDMD research.
- Further investigation is needed to address outstanding questions in the TDMD field.
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