Cell nonautonomous roles of NHR‐49 in promoting longevity and innate immunity

Abstract

Recent advances in aging research have led to a shift in focus from increasing life span to improving health span, a concept that encompasses measures of physiological health, including stress resistance

Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans

“…As described above, NHR-49::GFP imaging indicated that NHR-49 protein levels are induced in the intestine, neurons, and hypodermis during hypoxia ( Figure 2D , Figure 2—figure supplement 1E and F ). Hence, we asked if the expression of NHR-49 in any one of these tissues could rescue the hypoxia survival defects of the nhr-49 mutant ( Naim et al, 2021 ). Comparing the survival of each tissue-specific NHR-49::GFP rescue strain to their respective non-GFP siblings, we found that expressing nhr-49 in the intestine, neurons, hypodermis, body wall muscle, or from its endogenous promoter was sufficient to restore population survival to wild-type levels ( Figure 5B ).…”

“…However, recent studies indicate that stress response regulation requires the intricate interactions of multiple factors as part of networks that provide regulatory redundancy and flexibility. NHR-49 is a transcription factor that promotes longevity and development by regulating lipid metabolism and various stress responses ( Chamoli et al, 2014 ; Dasgupta et al, 2020 ; Goh et al, 2018 ; Naim et al, 2021 ; Wani et al, 2021 ). Our data show that NHR-49 coordinates a part of the transcriptional response to hypoxia.…”

“…nhr-49 is required to induce fmo-2 in various stresses and infection models ( Chamoli et al, 2014 ; Dasgupta et al, 2020 ; Goh et al, 2018 ; Naim et al, 2021 ; Wani et al, 2021 ). Similarly, HIF-1 regulates fmo-2 in several C. elegans longevity paradigms ( Leiser et al, 2015 ), and fmo-2 is induced in hypoxia, specifically 0.1% O 2 exposure, in a hif-1- dependent manner ( Leiser et al, 2015 ; Shen et al, 2005 ).…”

“…NHR-49 is expressed in the intestine, neurons, muscle, and hypodermis ( Ratnappan et al, 2014 ). Re-expression of nhr- 49 in any one of these tissues is sufficient to enhance worm survival upon infection with the pathogens S. aureus ( Wani et al, 2021 ) and to promote longevity in germline-less animals ( Naim et al, 2021 ), but NHR-49 acts only in neurons to promote survival upon infection by P. aeruginosa ( Naim et al, 2021 ). We thus aimed to identify the key tissue wherein NHR-49 promotes hypoxia survival.…”

“…By maintaining lipid homeostasis, NHR-49 is able to extend lifespan, a phenotype often associated with stress resistance ( Burkewitz et al, 2015 ; Ratnappan et al, 2014 ). In addition to regulating lipid metabolism, NHR-49 also regulates putative xenobiotic detoxification genes in a dietary restriction-like state and during starvation ( Chamoli et al, 2014 ; Goh et al, 2018 ), is required for resistance to oxidative stress ( Goh et al, 2018 ), and activates innate immune response programs upon infection of C. elegans with Staphylococcus aureus ( Wani et al, 2021 ), Pseudomonas aeruginosa ( Naim et al, 2021 ), and Enterococcus faecalis ( Dasgupta et al, 2020 ). Moreover, a recent report showed that nhr-49 is required to increase expression of the catechol-O-methyl-transferase comt-5 in hypoxia, acting downstream of the hypoxia-inhibited receptor tyrosine kinase hir-1 ( Vozdek et al, 2018 ).…”