A Family of Nuclear Argonaute Interacting Proteins Gates Nuclear RNAi

Nuclear RNA interference (RNAi) pathways work together with histone modifications to regulate gene expression and enact an adaptive response to transposable RNA elements. In the germline, nuclear RNAi can lead to trans-generational inheritance (TEI) of gene silencing. How the nuclear activities of RNAi are physiologically controlled remains poorly understood. Here, we identify and characterize a family of nuclear Argonaute-interacting proteins (NIPs) that control the strength and target specificity of nuclear RNAi in C. elegans, ensuring faithful inheritance of epigenetic memories. NIP-1 and NIP-2 prevent misloading of the nuclear Argonaute NRDE-3 with small RNAs that normally effect maternal piRNAs, which prevents precocious nuclear translocation of NRDE-3 in the early embryo. Additionally, NIP-1 and NIP-2 are negative regulators of nuclear RNAi triggered from exogenous sources (exo-RNAi). Loss of NIP-3, an unstable protein mostly expressed in the male germline, misdirects the RNAi response to transposable elements and impairs TEI.Our data support a model wherein NIPs determine the potency and specificity of nuclear RNAi responses by gating small RNAs into specific nuclear Argonautes in both somatic and germline tissues.