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Alterations in RNA processing during immune-mediated programmed cell death.

Danielle K Rajani¹, Michael Walch, Denis Martinvalet

¹Immune Disease Institute and Program in Molecular and Cellular Medicine, Children's Hospital Boston, Harvard Medical School, Boston MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America

|May 17, 2012

Summary

This summary is machine-generated.

Immune-mediated cell death targets nuclear RNA processing. Granzyme A (GzmA) degrades RNA-binding proteins, like heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), disrupting RNA export and splicing, promoting cell death.

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Published on: September 20, 2017

Area of Science:

Immunology
Molecular Biology
Cell Biology

Background:

Immune-mediated cell death involves granzyme (Gzm) proteases targeting cellular processes.
Nuclear localization of Gzm proteases suggests critical nuclear targets during immune elimination.

Purpose of the Study:

To identify nuclear substrates of Granzyme A (GzmA) using proteomic analysis.
To elucidate the role of GzmA-mediated degradation of RNA-binding proteins in immune cell death.

Main Methods:

Differential 2D proteomics of GzmA-treated nuclei to identify substrates.
Analysis of heterogeneous nuclear ribonucleoproteins (hnRNPs) degradation in various cell death pathways.
Assessment of RNA export and pre-mRNA splicing following GzmA or caspase activation.
Functional analysis using GzmA-resistant hnRNP A1 expression.

Main Results:

33 of 44 GzmA candidates were RNA-binding proteins involved in posttranscriptional RNA processing, including 14 hnRNPs.
Multiple hnRNPs were degraded during GzmA-, GzmB-, and caspase-mediated cell death.
GzmA and caspase activation inhibited nuclear RNA export and disrupted pre-mRNA splicing.
hnRNP A1 was identified as a key GzmA substrate, with its resistance to GzmA inhibiting cell death and rescuing splicing.

Conclusions:

Granzyme A targets RNA-binding proteins, particularly hnRNPs, in the nucleus during immune-mediated cell death.
Disruption of RNA processing by GzmA contributes to cell death by blocking protein synthesis and interfering with protective pathways.