Signatures of host–pathogen evolutionary conflict reveal MISTR—A conserved MItochondrial STress Response network

Host–pathogen conflicts leave genetic signatures in genes that are critical for host defense functions. Using these “molecular scars” as a guide to discover gene functions, we discovered a vertebrate-specific MItochondrial STress Response (MISTR) circuit. MISTR proteins are associated with electron transport chain (ETC) factors and activated by stress signals such as interferon gamma (IFNγ) and hypoxia. Upon stress, ultraconserved microRNAs (miRNAs) down-regulate MISTR1(NDUFA4) followed by replacement with paralogs MItochondrial STress Response AntiViral (MISTRAV) and/or MItochondrial STress Response Hypoxia (MISTRH). While cells lacking MISTR1(NDUFA4) are more sensitive to chemical and viral apoptotic triggers, cells lacking MISTRAV or expressing the squirrelpox virus-encoded vMISTRAV exhibit resistance to the same insults. Rapid evolution signatures across primate genomes for MISTR1(NDUFA4) and MISTRAV indicate recent and ongoing conflicts with pathogens. MISTR homologs are also found in plants, yeasts, a fish virus, and an algal virus indicating ancient origins and suggesting diverse means of altering mitochondrial function under stress. The discovery of MISTR circuitry highlights the use of evolution-guided studies to reveal fundamental biological processes.

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MISTR: A conserved MItochondrial STress Response network revealed by signatures of evolutionary conflict

10.1101/2020.01.25.919811 ◽

2020 ◽

Author(s):

Mahsa Sorouri ◽

Tyron Chang ◽

Palmy Jesudhasan ◽

Chelsea Pinkham ◽

Nels C. Elde ◽

...

Keyword(s):

Electron Transport Chain ◽

Rapid Evolution ◽

Biological Processes ◽

Algal Virus ◽

Evolutionary Conflict ◽

Transport Chain ◽

Response Network ◽

Stress Signals ◽

Genetic Signatures ◽

Host Genes

ABSTRACTHost-pathogen conflicts leave genetic signatures of variation in homologous host genes. Using these “molecular scars” as a guide, we discovered a vertebrate-specific MItochondrial STress Response circuit (MISTR). MISTR proteins are associated with electron transport chain factors and activated by stress signals such as interferon-gamma and hypoxia. Upon stress, ultraconserved miRNAs downregulate MISTR1 followed by replacement with paralogs MISTR AntiViral (MISTRAV) or MISTR Hypoxia (MISTRH), depending on the insult. While cells lacking MISTR1 are more sensitive to apoptotic triggers, cells lacking MISTRAV or expressing the poxvirus-encoded vMISTRAV exhibit resistance to the same insults. Rapid evolution signatures across primate genomes for MISTR1 and MISTRAV indicate ancient and ongoing conflicts with pathogens. MISTR proteins are also found in plants, yeasts, and an algal virus indicating ancient origins and suggesting diverse means of altering mitochondrial function under stress. The discovery of MISTR circuitry highlights the use of evolution-guided studies to reveal fundamental biological processes.

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Faculty Opinions recommendation of SLR-2 and JMJC-1 regulate an evolutionarily conserved stress-response network.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.2650956.2316054 ◽

2010 ◽

Author(s):

Christopher Schofield ◽

Christoph Loenarz

Keyword(s):

Stress Response ◽

Response Network ◽

Evolutionarily Conserved

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PARK2, A Large Common Fragile Site Gene, is Part of a Stress Response Network in Normal Cells that is Disrupted During the Ovarian Cancer

10.21236/ada452302 ◽

2005 ◽

Author(s):

David I. Smith

Keyword(s):

Ovarian Cancer ◽

Stress Response ◽

Fragile Site ◽

Common Fragile Site ◽

Normal Cells ◽

Response Network

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O‐GlcNAc controls mitochondrial quality control mechanisms and mitochondrial stress response proteins

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.03479 ◽

2021 ◽

Vol 35 (S1) ◽

Author(s):

Ibtihal Alghusen ◽

Heather Wilkins ◽

Chad Slawson

Keyword(s):

Quality Control ◽

Stress Response ◽

Control Mechanisms ◽

Mitochondrial Quality Control ◽

Mitochondrial Stress ◽

Stress Response Proteins

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FAST Is a Survival Protein That Senses Mitochondrial Stress and Modulates TIA-1-Regulated Changes in Protein Expression

Molecular and Cellular Biology ◽

10.1128/mcb.24.24.10718-10732.2004 ◽

2004 ◽

Vol 24 (24) ◽

pp. 10718-10732 ◽

Cited By ~ 41

Author(s):

Wei Li ◽

Maria Simarro ◽

Nancy Kedersha ◽

Paul Anderson

Keyword(s):

Protein Synthesis ◽

Rna Interference ◽

Stress Response ◽

Mitochondrial Membrane ◽

Binding Domain ◽

Outer Mitochondrial Membrane ◽

Mitochondrial Stress ◽

Inhibitors Of Apoptosis ◽

Reporter Proteins ◽

Induced Apoptosis

ABSTRACT The Fas-activated serine/threonine phosphoprotein (FAST) is tethered to the outer mitochondrial membrane, where it interacts with BCL-XL (17). Here we show that RNA interference-mediated knockdown of endogenous FAST results in apoptosis, whereas overexpressed recombinant FAST inhibits Fas- and UV-induced apoptosis, indicating that FAST is a survival protein. The antiapoptotic effects of FAST are regulated by interactions with the translational silencer TIA-1: a FAST mutant lacking its TIA-1-binding domain does not inhibit apoptosis, and overexpressed recombinant TIA-1 inhibits the antiapoptotic effects of FAST. Because the antiapoptotic effects of FAST require ongoing protein synthesis, we hypothesized that FAST might function by preventing TIA-1-mediated silencing of mRNAs encoding inhibitors of apoptosis. Consistent with this hypothesis, FAST promotes the expression of cotransfected reporter proteins, a process that requires its TIA-1-binding domain and is inhibited by overexpressed recombinant TIA-1. More compellingly, recombinant FAST increases the expression of endogenous cIAP-1 and XIAP, but not GAPDH, in transfected HeLa cells. Because FAST is released from mitochondria in cells undergoing Fas- or UV-induced apoptosis, we propose that FAST serves as a sensor of mitochondrial stress that modulates a TIA-1-regulated posttranscriptional stress response program.

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