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Cell Death Differ. 2019 Feb 6. doi: 10.1038/s41418-019-0291-z. [Epub ahead of print]

MINA-1 and WAGO-4 are part of regulatory network coordinating germ cell death and RNAi in C. elegans.

Author information

1
Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
2
PhD Program in Molecular Life Sciences, University of Zurich and ETH Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
3
Institute of Pharmaceutical Sciences, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093, Zürich, Switzerland.
4
Institute of Molecular Biology and Biophysics, ETH Zurich, Auguste-Piccard-Hof 1, 8093, Zurich, Switzerland.
5
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
6
University Children's Hospital Basel, University of Basel, Spitalstrasse 33, 4056, Basel, Switzerland.
7
Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056, Basel, Switzerland.
8
Department of Pathology, NYU School of Medicine, New York, NY, 10016, USA.
9
Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, 10016, USA.
10
Institute of Molecular Systems Biology, ETH Zurich, Auguste-Piccard-Hof 1, 8093, Zurich, Switzerland.
11
RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.
12
Center for Microscopy and Image Analysis, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
13
Department of Microbial and Cellular Sciences, Faculty of Health and Medical Sciences, University of Surrey, Stag Hill Campus 19 AX 01, GU2 7XH, Guildford, UK.
14
Faculty of Science, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
15
Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland. michael.hengartner@imls.uzh.ch.
16
Faculty of Science, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland. michael.hengartner@imls.uzh.ch.

Abstract

Post-transcriptional control of mRNAs by RNA-binding proteins (RBPs) has a prominent role in the regulation of gene expression. RBPs interact with mRNAs to control their biogenesis, splicing, transport, localization, translation, and stability. Defects in such regulation can lead to a wide range of human diseases from neurological disorders to cancer. Many RBPs are conserved between Caenorhabditis elegans and humans, and several are known to regulate apoptosis in the adult C. elegans germ line. How these RBPs control apoptosis is, however, largely unknown. Here, we identify mina-1(C41G7.3) in a RNA interference-based screen as a novel regulator of apoptosis, which is exclusively expressed in the adult germ line. The absence of MINA-1 causes a dramatic increase in germ cell apoptosis, a reduction in brood size, and an impaired P granules organization and structure. In vivo crosslinking immunoprecipitation experiments revealed that MINA-1 binds a set of mRNAs coding for RBPs associated with germ cell development. Additionally, a system-wide analysis of a mina-1 deletion mutant compared with wild type, including quantitative proteome and transcriptome data, hints to a post-transcriptional regulatory RBP network driven by MINA-1 during germ cell development in C. elegans. In particular, we found that the germline-specific Argonaute WAGO-4 protein levels are increased in mina-1 mutant background. Phenotypic analysis of double mutant mina-1;wago-4 revealed that contemporary loss of MINA-1 and WAGO-4 strongly rescues the phenotypes observed in mina-1 mutant background. To strengthen this functional interaction, we found that upregulation of WAGO-4 in mina-1 mutant animals causes hypersensitivity to exogenous RNAi. Our comprehensive experimental approach allowed us to describe a phenocritical interaction between two RBPs controlling germ cell apoptosis and exogenous RNAi. These findings broaden our understanding of how RBPs can orchestrate different cellular events such as differentiation and death in C. elegans.

PMID:
30728462
DOI:
10.1038/s41418-019-0291-z

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