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. 2020 Jul 13;9(4):461–466. doi: 10.1093/toxres/tfaa041

Ultraviolet light activates PMK-1/p38 MAPK signaling via MOM-4 and JKK-1 in Caenorhabditis elegans

Jing Ma 1, Xinghao Jiang 2, An Yarui 3, Jin Danli 3, Yin Xiaodie 3, Jian Zhang 1,✉, Ajing Xu 1,✉
PMCID: PMC7467232  PMID: 32905206

Abstract

P38 mitogen-activated protein kinase (p38 MAPK) plays an important role in innate immunity and is activated by ultraviolet (UV) radiation. However, the molecular mechanism underlying UV stress remains unclear. In this study, we reported that UV activated PMK-1/p38 MAPK signaling via JKK-1 and MOM-4 in Caenorhabditis elegans. In C. elegans, different UV radiation doses resulted in PMK-1 phosphorylation. However, pmk-1 mutants failed to demonstrate an altered survival time in response to UV when compared with wild-type worms. Further analysis showed that JKK-1, but not SEK-1 mutants, displayed impaired PMK-1 activation following UV irradiation, suggesting that JKK-1 is the upstream MAP2K for the activation of PMK-1 in C. elegans under UV stimulation. UV-induced activation of PMK-1 was markedly reduced in MOM-4, but not in NSY-1 and DLK-1 mutant worms, suggesting that MOM-4 is the upstream MAP3K regulator of PMK-1 activation in response to UV stress in C. elegans. Additionally, daf-16 mutants displayed a shorter lifespan under UV stress, but UV-induced activation of PMK-1 was not markedly reduced in daf-16 and age-1 mutant worms. Our results revealed the signaling pathway involved in PMK-1 activation in C. elegans in response to UV radiation.

Keywords: C. elegans, ultraviolet, JKK-1, PMK-1, MOM-4

Introduction

Ultraviolet (UV) radiation is an environmental carcinogen with diverse biological effects, including cellular aging, immune suppression, and initiation of apoptosis. UV radiation triggers inflammatory and immunological reactions through the induction of DNA/RNA damage and promotes the generation of reactive oxygen species (ROS) [1, 2]. In BALB/c mice, UVB radiation induces oxidative stress and inflammatory processes [3]. In human skin cells, UVB induces the phosphorylation of signaling molecules and inflammation through p38 mitogen-activated protein kinase (p38 MAPK) signaling [4]. Furthermore, the generation of ROS and the activities of matrix metalloproteinase-1 (MMP-1)/MMP-4 are induced by UVB in HaCaT cells via MAPK signaling [5]. UVB exposure increases skin thickness, collagen fragmentation, and MMP expression in hairless mice, inducing the phosphorylation of MAPKs, including extracellular signal-regulated kinases (ERK) and p38, activator protein (AP-1) subunit, as well as the signal transduction and activation of transcription 1 (STAT1). In SKH-1 mice, UVB irradiation of murine skin activates epidermal p38 MAPK signaling and induces a local pro-inflammatory response [6]. In p38 dominant-negative (p38DN) transgenic mice, UVB-induced AP-1 activation, as well as tumor number and growth, were reportedly inhibited when compared with wild-type mice [7]. Moreover, in cultured keratinocytes and mouse skin, inhibition of p38 MAPK signaling suppresses UVB-induced cyclic AMP response element-binding protein (CREB) phosphorylation and c-fos expression [8]. The MAPK pathway could play an important role in initiating and eliciting a response by the host against UVA exposure [9]. UV irradiation can induce skin cancer cell autophagy via the p38 signal pathway [10]. Notably, the p38–MK2 signaling axis regulates RNA metabolism after UV light-induced DNA damage [11]. These findings demonstrate that p38 MAPK signaling is activated in response to UV radiation; however, the precise molecular mechanism needs to be elucidated.

Previously, studies have revealed that activation of the NSY-1/SEK-1/PMK-1 (p38 MAPK) MAP kinase cascade is essential for Caenorhabditis elegans to respond to pathogen attacks [12]. In mammals, activation of p38 MAPK is usually mediated by upstream MAP2Ks, MKK3, and MKK6 [13–15]. Additionally, it has been demonstrated that MKK4, MKK3, and MKK6 are required for UV-induced p38 MAPK activation [16–18]. Other signaling pathways, including NFκB, PI3K/AKT, and TNF alpha signal transduction pathways, are also involved in UV stress responses [19]. Our previous study has demonstrated that PMK-1 signaling is activated in C. elegans by numerous inflammatory mediators and environmental stressors and different MAP2Ks and MAP3Ks partially regulate the activation of PMK-1 during pathogen stress [20]. C. elegans MOM-4 (MAP3K) is required for the activation of the p38 MAPK signaling pathway in response to the development of a Pseudomonas infection. C. elegans JKK-1 (MAP2K) is required for the oxidative stress response induced by silver nanoparticle exposure [21]. However, the roles of MAP2Ks and MAP3Ks in PMK-1 activation during UV stress need to be comprehensively characterized.

In this study, we investigated the effect of UV irradiation on the p38 MAPK pathway and determined the functions of different MAP2Ks and MAP3Ks in the activation of p38 MAPK in response to UV exposure in C. elegans.

Materials and Methods

Worm strains and culture

Strains N2, NL2099 rrf-3 (pk1426) II, CX4998 (kyIs140) I, nsy-1 (ky397) II, CZ4213 mkk-4 (ju91) X, CZ5730 dlk-1 (ju476) I, EU446, unc-13 (e1091) mom-4 (or39) I/hT2 (I;III), FK171 mek-1 (ks54) X, KU2 jkk-1 (km2) X, KU4 sek-1 (km4) X, KU25 pmk-1 (km25) IV, TJ1052 age-1 (hx546) II, and daf-16 (mu86) were obtained from the Caenorhabditis Genetics Center (CGC). Nematodes were handled using standard methods with a few modifications. We used Escherichia coli OP50-1, a streptomycin-resistant variant strain of OP50, as the food source for the worm strains to avoid possible contamination by other microbes. OP50-1 was also obtained from CGC.

Bacteria-mediated RNAi

Bacteria-mediated RNAi was performed as previously described. Eggs derived from bleach-synchronized gravid adult worms were hatched in M9 buffer at 20°C for 12 h, and then L1 worms were transferred to RNAi plates seeded with E. coli strain HT115. HT115 was transformed with the L4440 vector or specific genomic DNA fragments in advance. RNAi plates contained 1 mM IPTG, in addition to 50 μg/ml of ampicillin in NGM plates. Worms were grown to the L4 or young adult stage at 20°C and used in the following assays. Genomic DNA fragments of specific genes were cloned using primers listed in the WormBase C. elegans genomic clones (www.wormbase.org).

The primers used in this study were as follows:

daf-16, F: ctagAAGCTTCTATTGAGACGACTACAAAGGTA

R: ctagCTCGAGTGGTGGAGCAATTGGTTCCGT

pmk-1, F: ctagAAGCTTGTGCTGCTGAATGTACTCGC

R: ctagCTCGAGTCTGGAAATCACTGATCTCTTCC

unc-22, F: actgctgcagCACTCTTACTGCTACCAACGCTT

R: atcgccatggAATGATCTCCCTTGTTGAGTGAA

DNA fragments were cloned into the L4440 plasmid, and RNAi experiments were performed as previously described. The unc-22 gene was used as the control for observing RNAi efficiency. RNAi-treated worms were washed with M9 buffer and used for the following assays.

Worm stress

UV stress assays were performed as previously described. All assays were performed with L4 or young adult stage hermaphrodites unless otherwise noted. Briefly, UV stress assays were performed with a UV dose of 1200 J/cm2 (HL-2000 HybriLinker, UVP, LLC, USA) as previously described. For UV irradiation assays, eggs from sterile strains of N2 and mutants were transferred to plates. Worms were grown in the L1 stage at 20°C and shifted to 25°C to ensure their infertility and growth to D1 adulthood. Then, worms were transferred to plates without food and exposed to a UV dose of 1200 J/cm2 using a UV Stratalinker. After UV stress, worms were transferred back to fresh plates and scored daily for viability. Treated worms were checked and counted to assess viability and were scored as dead without response following at least three gentle prods with a platinum wire. Assays were performed at 25°C, with three plates per strain tested for each experiment.

Lifespan assays

Lifespan assays were performed as previously described. Gravid adult worms were synchronized using the bleach method. Eggs were hatched and grown to the L4 or young adult stage at 20°C on NGM plates. Then, approximately 20–30 animals were transferred onto each NGM plate seeded with OP50-1, and 100 μg/ml of 5-fluorodeoxyuridine (FUDR) was added to the NGM plates. Assays were performed at 25°C, with three plates per strain evaluated for each experiment. To test if the animals were alive or dead, worms were scored every 2 days by gently prodding them with a platinum wire. Death and lifespan data, as well as the plots drawn for this study, were calculated using Origin 7.5.

SDS-PAGE and immunoblot analysis

Immunoblot analyses were performed as previously described with a few modifications. Briefly, worms treated with various stresses were lysed in 2× Laemmli sample buffer, followed by the addition of proteasome and phosphatase cocktail inhibitors (Sigma), and frozen immediately in liquid nitrogen (LN2). Then, the samples were boiled at 100°C for 10 min. Protein concentration was determined using a BCA kit (Beyotime, Haimen, China). Equal amounts of protein samples were resolved by SDS-PAGE (10% gels) and transferred to nitrocellulose membranes. The membranes were blocked with gelatin and subjected to antibody incubation. P38 T180/Y182 phospho-specific antibodies recognizing doubly phosphorylated PMK-1 were obtained from Biosource (Camarillo, CA, USA). The anti-α-tubulin (Sigma) antibody was used as a loading control.

Results

PMK-1/p38 MAPK is activated by UV in C. elegans

Previously, studies have shown that mammalian p38 MAPK is strongly activated by UV radiation, playing important roles in regulating cellular responses to UV [9]. To analyze the functions of the C. elegans PMK-1/p38 signaling pathway in response to UV radiation, we first determined whether PMK-1 could be activated by UV stress. Wild-type C. elegans strain N2 worms were exposed to UV stress, and the activation of PMK-1 was detected using a p38 T180/Y182 phospho-specific antibody. As shown in Fig. 1, the stimulation of N2 worms with a UV dose of 1200 J/cm2 induced robust PMK-1 activation as early as 5 min after UV irradiation. PMK-1 activation peaked at 30 min and gradually recovered after UV irradiation. These results revealed that UV radiation activated the C. elegans p38 MAPK homolog PMK-1 and suggest that PMK-1/p38 plays a role in C. elegans response to UV stimuli.

Figure 1.

Figure 1

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Activation of C. elegans p38 homolog PMK-1 by UV. Young adult N2 worms were exposed to a UV dose of 1200 J/cm2 and cultured in M9 buffer for the indicated time. Following treatment, worms were collected in M9 buffer, lysed, and analyzed by western blotting. PMK-1 activation was detected by blotting with anti-phospha-p38 antibody with α-tubulin as loading control. Data shown represent at least three independent experiments.

PMK-1 signaling is not essential for the survival of C. elegans under UV stress

PMK-1 could be activated by 300–2000 J/cm2 UV doses (Supplementary Fig. 1). To examine whether PMK-1 plays a key role in the UV stress response of C. elegans, wild-type N2 worms, daf-16 (insulin-like growth factor, IGF-1) mutant worms (mu86, as control), or PMK-1 mutant worms (km25) were stimulated with UV, followed by survival analysis. At a UV dose of 1200 J/cm2, we observed that the PMK-1 mutant worm strain, km25, exhibited a relatively similar survival rate as the wild-type N2 worm. In contrast, the daf-16 mutant worm strain, mu86, demonstrated a shorter survival time than wild-type N2 did with a UV dose of 1200 J/cm2 (Fig. 2A). Consistently, PMK-1 RNAi-treated worms exhibited similar survival times as wild-type worms, while daf-16 RNAi-treated worms exhibited higher susceptibility at a UV dose of 1200 J/cm2 (Fig. 2B).

Figure 2.

Figure 2

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Activation of the PMK-1 signaling pathway was not involved in UV-induced worm survival. (A) Viability of N2, PMK-1 (km25), and daf-16 (mu86) mutant worms to UV stress. (B) Viability of bacterial-mediated RNAi treated NL2099 worms to UV stress. L4440 vector-, L4440–daf-16-, and L4440–PMK-1-treated worms were exposed to a UV dose of 1200 J/cm2, and worms were counted every 24 h.

JKK-1 regulates PMK-1 activation under UV stress

To determine which of the MAP2Ks plays a role in the activation of PMK-1 under UV stress, we used different genetic mutants of MEK-1, JKK-1, and SEK-1 to analyze the activation of PMK-1/p38 in response to UV irradiation. Both MEK-1 and SEK-1 mutants demonstrated potent PMK-1 activation in response to UV stimulation when compared to wild-type worms, suggesting that MEK-1 and SEK-1 are not essential for PMK-1 activation following UV stress in C. elegans. Conversely, JKK-1 mutants (km2) revealed significantly impaired PMK-1 activation following UV irradiation (Fig. 3). These results suggest that JKK-1 is required for PMK-1 activation in C. elegans following UV stimulation.

Figure 3.

Figure 3

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Activation of C. elegans PMK-1 depended on JKK-1 in response to UV. N2 and mutant worm strains MEK-1 (ks54), KU4 SEK-1 (km4), FK171 KU2 JKK-1 (km2), and PMK-1 (km25) were either untreated or exposed to a UV dose of 1,200 J/cm2, and worm extracts were harvested 30 min after radiation. Worm extracts were immunoblotted with anti-phospho-PMK-1 to detect PMK-1 activation, and anti-α-tubulin to detect total protein. Data shown represents at least three independent experiments.

MOM-4 regulates PMK-1 activation under UV stress

The NSY-1, SEK-1, and PMK-1 pathways play a central role in innate immune responses to pathogenic infections [12]. To investigate whether MAP3Ks, NSY-1, and MOM-4 are involved in PMK-1 activation in response to UV, we compared the activation of PMK-1 among NSY-1, MOM-4, DLK-1 (ju476, another MAP3K homolog), and N2 worms challenged with UV stress. Compared to that in the wild-type N2 worms, the UV-induced PMK-1 activation was markedly reduced in MOM-4, but not in NSY-1 (ky397) and DLK-1 (ju476) mutant worms (Fig. 4), suggesting that MOM-4 regulates PMK-1 activation in response to UV stress in C. elegans.

Figure 4.

Figure 4

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Mutation of MAP3K and MOM4 apparently reduced the activation of PMK-1 in response to UV in C. elegans. N2 and mutant worm strains CX4998 (nsy-1, ky397), CZ5730 DLK-1 (ju476), and EU446 (mom-4, or49) were treated with a UV dose of 1200 J/cm2. Worm extracts were immunoblotted with anti-phospho-PMK-1 to detect PMK-1 activation and with anti-α-tubulin to detect total protein. Data shown represent at least three independent experiments.

C. elegans daf-16 and age-1 are not required for UV stress

Our results revealed that the daf-16 mutant worm strain, CF1038 (mu86), and daf-16 RNAi-treated worms exhibited high susceptibility to UV radiation (Fig. 2), indicating the involvement of daf-16 in modulating the lifespan of C. elegans. AGE-1, the worm homolog of mammalian phosphoinositide 3-kinase (PI3K), regulates the daf-16 lifespan, while JKK is the upstream kinase of JNK-1, and JNK-1 is a positive regulator of daf-16 [22]. To assess whether the daf-16 pathway is involved in UV-induced PMK-1 activation, we used daf-16 and age-1 mutant worms to analyze the activation of PMK-1 under UV stress. As shown in Fig. 5, UV-induced PMK-1 activation was not markedly reduced in daf-16 and age-1 mutant worms when compared with wild-type N2 and NSY-1 worms, suggesting that daf-16 and age-1 do not regulate PMK-1 activation in response to UV stress.

Figure 5.

Figure 5

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Daf-16 and age-1 were not required for PMK-1 activation in response to UV stimuli in C. elegans. C. elegans N2 strains, as well as NSY-1 (ky397), KU25 PMK-1 (km25), daf-16 (mu86), and age-1 (hx546) II mutant strains, were treated with a UV dose of 1200 J/cm2, with mutant worm strain CX4998 (nsy-1, ky397) as control. Worm extracts were immunoblotted with anti-phospho-PMK-1 to detect PMK-1 activation and with anti-α-tubulin to detect total protein. Data shown represent at least three independent experiments.

Discussion

In this study, we demonstrated that the C. elegans p38 MAPK homolog, PMK-1, was activated in response to UV stimuli. Further mechanistic investigations utilizing different mutants of MAPK signaling components revealed that MOM-4 (MAP3K) and JKK-1 (MAP2K) were upstream regulators of PMK-1 activation in response to UV irradiation.

MAPK signaling cascades are targets for UV and are crucial for regulating a multitude of UV-induced cellular responses [9]. The MAPK family consists of ERKs, c-Jun N-terminal kinases (JNKs), and p38 kinase [23]. Previous studies have demonstrated that the transfer of signals between MAPK and its immediate upstream kinase (MAPKK) is highly specific. P42/p44 (ERK) MAP kinases are exclusively phosphorylated by MAP/ERK kinase (MEK) 1 and 2, p38 MAP kinase is selectively activated by MAP kinase kinases (MKKs) 3 and 6, while JNK is activated by MKK7 and MKK4 [13, 14, 18]. Our study revealed that the MAP2K JKK-1, a mammalian MKK-7 homolog of C. elegans, was required for PMK-1 activation in response to UV stress in C. elegans; however, MEK-1 mutants demonstrated no apparent alteration in PMK-1 activation under UV stress. Our results suggest that JKK-1 is involved in the resistance of C. elegans to UV through PMK-1 pathways; however, whether JKK-1 regulates responses in C. elegans to UV by the activation of other MAPKs, such as JNK-1, remains unknown.

The NSY-1/SEK-1/PMK-1 pathway plays a central role in the innate immune response to pathogenic infections in C. elegans. However, in the case of diverse genetic mutants of MAP3Ks, including NSY-1, MEK-1, DLK-1, and MOM-4, we observed that the UV-induced PMK-1/p38 activation significantly reduced MOM-4 mutants. Furthermore, we observed that neither NSY-1 nor MEK-1 regulated PMK-1 activation in response to UV irradiation. Moreover, for the first time, we demonstrated that MOM-4, a homolog of mammalian TAK1, was involved in the resistance of C. elegans to UV stress by regulating PMK-1 activation. Reportedly, MOM-4 plays an important role in regulating GO-induced reproductive failure in in vivo systems [24]. MOM-4 is activated by direct phosphorylation within the activation loop [25]. Our research suggests that MOM-4 and MAP3Ks are essential for UV-induced p38 MAPK activation in C. elegans. However, whether MOM-4 regulates PMK-1 activation via JKK-1 needs to be determined.

JKK-1 is the upstream kinase of JNK-1, and JNK-1 is a positive regulator of daf-16. Daf-16 is a forkhead transcription factor and downstream target of insulin-like signaling in C. elegans confirmed to be indispensable for both lifespan regulation and stress resistance [22]. Our results demonstrated that the daf-16 mutant worm strain CF1038 (mu86) and daf-16 RNAi-treated worms exhibited higher susceptibility to UV radiation. We analyzed the activation of PMK-1 in daf-16 and age-1 mutant worms challenged with UV stress, demonstrating that daf-16 and age-1 did not affect PMK-1 activation in C. elegans under UV stress. A previous study has suggested that oxidative stress mediates the regulation of daf-16 through the activation of the p38 signal transduction pathway upstream of daf-16, mobilizing daf-16 to the nucleus and activating transcription [26]. Thus, it is possible that JKK-1 independently regulates the UV response in C. elegans through PMK-1, via an insulin-like signaling pathway. Consistent with previous observations, in which MAPK pathways play important roles in UV-induced cell damage, our genetic analysis indicated that both the MAPK pathway and insulin-like signaling pathway may regulate responses to UV stress in C. elegans. Considering the crucial role of JKK-1 in UV-induced PMK-1 activation in C. elegans, our results suggest that JKK-1 could be essential for crosstalk among these processes and molecular inhibitors of JKK-1 could modulate UV-induced DNA damage.

In summary, UV radiation resulted in PMK-1 activation, and MOM-4 and JKK-1 were required for PMK-1 activation in response to UV irradiation. Our findings suggest that small molecular inhibitors of MOM-4 and JKK-1 could attenuate inflammatory and immunological responses induced by UV irradiation.

Supplementary Material

Supplement_Figure1_tfaa041
Click here for additional data file. (132.7KB, png)

Funding

This project was partially supported by a grant from the National Natural Science Foundation of China (No. 81200044, No. 81402904), the Science and Technology Commission of Shanghai Municipality (No. 13ZR1426900, No. 15411963900), the Innovation program of Shanghai Municipal Education Commission (No. 12ZZ117), and the Biomedical Engineering Cross-fund of Shanghai Jiaotong University (No. YG2012MS57).

Conflict of interest statement

None declared.

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Associated Data

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Supplementary Materials

Supplement_Figure1_tfaa041
Click here for additional data file. (132.7KB, png)

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