The subcellular topology of the RNAi machinery is multifaceted and reveals adherens junctions as an epithelial hub

TL;DR

This study reveals that the RNAi machinery has a complex subcellular organization, with RNAi components localized at cell junctions in healthy epithelial cells but not in transformed or mesenchymal cells.

Contribution

The study identifies a novel junctional localization of RNAi machinery at adherens junctions in well-differentiated epithelial cells.

Findings

Junctional localization of RNAi components is common in well-differentiated epithelia but absent in transformed or mesenchymal cells.

The microprocessor is found in the cytoplasm, and RISC is localized in the nucleus, challenging traditional models.

RNAi complexes associate with adherens junctions via PLEKHA7, an E-cadherin partner.

Abstract

The RNA interference (RNAi) machinery is a key cellular mechanism catalyzing
biogenesis and function of miRNAs to post-transcriptionally regulate mRNA expression. The
RNAi machinery includes a set of protein complexes with subcellular localization
traditionally presented in a uniform fashion: the microprocessor processes miRNAs in the
nucleus, whereas the DICER and the RNA-induced silencing complex (RISC) further process
and enable activity of miRNAs in the cytoplasm. However, several studies have identified
subcellular patterns of RNAi components that deviate from this model. We have particularly
shown that RNAi complexes associate with the adherens junctions of well-differentiated
epithelial cells, through the E-cadherin partner PLEKHA7. To assess the extent of these
subcellular topological patterns, we examined subcellular localization of the
microprocessor and RISC in a series of human cell lines and normal human tissues. Our
results show that junctional localization of RNAi components is a broad characteristic of
well-differentiated epithelia, but it is absent in transformed or mesenchymal cells and
tissues. We also find extensive localization of the microprocessor in the cytoplasm, as
well as of RISC in the nucleus. These findings expose a RNAi machinery with multifaceted
subcellular topology that may inform its physiological role and calls for updating of the
current models.

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