Selective autophagy degrades DICER and AGO2 and regulates miRNA activity

Abstract

Micro (mi)RNAs form a class of short RNAs (~21 nt) that post-transcriptionally regulate partially complementary messenger (m)RNAs. Each miRNA may target tens-to-hundreds of transcripts to control key biological processes. While the biochemical reactions underpinning miRNA biogenesis and activity are relatively well-defined1,2, and the importance of their homeostasis increasingly evident, the processes underlying regulation of miRNA pathways in vivo are still largely elusive3. Autophagy, a degradative process in which cytoplasmic material is targeted into double-membrane vacuoles, is recognized to critically contribute to cellular homeostasis. Here, we show that the miRNA-processing enzyme, DICER, and the major miRNA effector, AGO2, are targeted for degradation as miRNA-free entities by the selective autophagy receptor NDP52. Autophagy establishes a checkpoint required for continued loading of miRNA into AGO2; accordingly, NDP52 and autophagy are required for homeostasis and activity of tested miRNAs. Autophagy also engages post-transcriptional regulation of the DICER mRNA, underscoring the importance of fine-tuned regulation of the miRNA pathway. These findings have implications for human diseases linked to misregulated autophagy, DICER- and miRNA-levels, including cancer.

Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function

“…For example, miRNAs have recently emerged as critical regulators of immune cell development and function (41). Expression of Dicer, an essential component of miRNA biogenesis, appears to be dependent on mTORC1 activity (42). miRNA networks have been found to regulate iNKT-cell development and/or function (43-47), but whether mTORC1 promotes iNKT maturation via miRNAs remains to be determined.…”

The epigenetic regulation of Dicer and microRNA biogenesis by Panobinostat

“…Distinct pathways, including autophagy, apoptosis, and hypoxia can regulate Dicer expression. 26,42,[44][45][46] Additionally, transcription factors such as MITF, SOX4, and NF-kB interact with the DICER promoter to regulate its expression. [47][48][49] Since Dicer levels are frequently altered in disease states, determining the mechanisms of Dicer regulation and dysregulation will be of paramount importance.…”

MicroRNA and autophagy—C. elegans joins the crew

“…The recent demonstration, in both human cells and plants, that autophagy is indeed an integral part of miRNA homeostasis [1,2], prompted Zhang and Zhang to explore whether the same was true in C. elegans. They first used a reverse genetic approach based on well-characterized developmental defects shown by animals defective for miRNA biogenesis or action, including the reiteration of stage-specific cell proliferation programmes known as 'heterochronic' defects.…”

“…In fact, this endeavour should be considered a priority if the various tenants of miRNA biology are to be fully understood through modifier gene identification but also interactome studies. A second interesting aspect emerging from the work of Zhang and Zhang, and others [1,2], is the notion that autophagy is part of a global homeostatic regulatory mechanism that prevents overt perturbations to the miRNA pathway. Whilst such perturbations might be artificially induced genetically, as in the present study, they will probably arise naturally through various stresses of abiotic or biotic origin.…”

“…Whether these effects are mediated through alterations of autophagy or other membranebased miRNA regulatory processes, and whether pathogen virulence factors can be used as molecular probes of the underlying mechanisms, are interesting prospects for future investigation. A strocytes have important roles in the brain, for example by regulating neuro transmitter clearance, controlling the formation and maintenance of synapses, and by contributing to the bloodbrain barrier (BBB; for a review see [1]). In addition, astrocytes respond to acute and chronic injury by hypertrophy and induced proliferation.…”