The Caenorhabditis elegans ARIP-4 DNA helicase couples mitochondrial surveillance to immune, detoxification, and antiviral pathways

Abstract

Surveillance of Caenorhabditis elegans mitochondrial status is coupled to defense responses such as drug detoxification, immunity, antiviral RNA interference (RNAi), and regulation of life span. A cytochrome p540 detoxification gene, cyp-14A4 , is specifically activated by mitochondrial dysfunction. The nuclear hormone receptor NHR-45 and the transcriptional Mediator component MDT-15/MED15 are required for the transcriptional activation of cyp-14A4 by mitochondrial mutations, gene inactivations, or toxins. A genetic screen for mutations that fail to activate this cytochrome p450 gene upon drug or mutation-induced mitochondrial dysfunction identified a DNA helicase ARIP-4 that functions in concert with the NHR-45 transcriptional regulatory cascade. In response to mitochondrial dysfunction, ARIP-4 and NHR-45 protein interaction is enhanced, and they relocalize from the nuclear periphery to the interior of intestinal nuclei. NHR-45/ARIP-4 also regulates the transcriptional activation of the eol-1 gene that encodes a decapping enzyme required for enhanced RNAi and transgene silencing of mitochondrial mutants. In the absence of arip-4 , animals were more susceptible to the mitochondrial inhibitor antimycin. Thus, ARIP-4 serves as a transcriptional coactivator of NHR-45 to promote this defense response. A null mutation in arip-4 extends the life span and health span of both wild type and a mitochondrial mutant, suggesting that the activation of detoxification pathways is deleterious to health when the mitochondrial dysfunction is caused by mutation that cannot be cytochrome p450-detoxified. Thus, arip-4 acts in a pathway that couples mitochondrial surveillance to the activation of downstream immunity, detoxification, and RNAi responses.

DKK2 promotes the progression of oral squamous cell carcinoma through the PI3K/AKT signaling pathway

“…One of the characteristics of solid malignant tumors is the relative hypoxia within the tumor mass [ 26 , 27 ]. This is because rapidly growing malignant tumors disrupt the balance between oxygen consumption and supply, leading to a hypoxic environment inside cancer cells.…”

R-loop resolution by ARIP4 helicase promotes androgen-mediated transcription induction

“…In this study, we show that the AR coactivator AR-interacting protein 4 (ARIP4) (23)(24)(25)(26) plays a part in androgen-dependent DSB formation and transcription induction. Originally identified as an SNF2 helicase family of chromatin remodelers, ARIP4 binds and hydrolyses adenosine triphosphate (ATP) in the presence of DNA, although the helicase showed no remodeling activity under conditions tested (27).…”

Activation of intestinal immunity by pathogen effector-triggered aggregation of lysosomal TIR-1/SARM1

“…8 We found that a C. elegans nuclear hormone receptor (NHR-86) binds phenazine-1-carboxamide (PCN), a virulence effector produced by the bacterial pathogen Pseudomonas aeruginosa, and directly activates innate immune defenses. 8 Additionally, pathogen-induced disruption of host translation, [9][10][11] mitochondrial respiration, [12][13][14] and the proteasome, 15,16 as well as cell damage 17 and physical distention of the intestinal lumen, [18][19][20] activate innate immune defenses.…”

“…For example, C. elegans uses a non-canonical pattern recognition system to intercept pathogen-derived metabolite signatures of bacterial growth and virulence to evaluate the threat posed by environmental pathogens. 20 Additionally, pathogeninduced disruption of host translation, [21][22][23] mitochondrial respiration, [24][25][26] and the proteasome, 27,28 as well as cell damage 29 and physical distention of the intestinal lumen, [30][31][32] activate innate immune defenses. In this context, the conservation of a TIR protein with NADase activity in innate immunity is noteworthy in an animal that does not utilize TIR domain-containing TLRs as pattern recognition receptors.…”