Urm1: an essential regulator of JNK signaling and oxidative stress in Drosophila melanogaster

Khoshnood, Behzad; Dacklin, Ingrid; Grabbe, Caroline

doi:10.1007/s00018-015-2121-x

Cited by 26 publications

(42 citation statements)

References 70 publications

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“…This result contrasts with some studies showing that JNK activity is necessary for UVR-induced apoptosis145960. However, our results are consistent with studies suggesting that JNK is also a key modulator of oxidative stress-mediated cell survival14606162. Discrepancies between studies may be explained by the use of different UV sources: whereas a UVA/B source that reproduces the UVR solar spectrum was used in our study, cells were exposed to UVC in the aforementioned studies145960.…”

Section: Discussionsupporting

confidence: 53%

The c-Jun N-terminal kinase prevents oxidative stress induced by UV and thermal stresses in corals and human cells

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Grover

et al. 2017

Sci Rep

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Coral reefs are of major ecological and socio-economic interest. They are threatened by global warming and natural pressures such as solar ultraviolet radiation. While great efforts have been made to understand the physiological response of corals to these stresses, the signalling pathways involved in the immediate cellular response exhibited by corals remain largely unknown. Here, we demonstrate that c-Jun N-terminal kinase (JNK) activation is involved in the early response of corals to thermal and UV stress. Furthermore, we found that JNK activity is required to repress stress-induced reactive oxygen species (ROS) accumulation in both the coral Stylophora pistillata and human skin cells. We also show that inhibiting JNK activation under stress conditions leads to ROS accumulation, subsequent coral bleaching and cell death. Taken together, our results suggest that an ancestral response, involving the JNK pathway, is remarkably conserved from corals to human, protecting cells from the adverse environmental effects.

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Section: Discussionsupporting

confidence: 53%

The c-Jun N-terminal kinase prevents oxidative stress induced by UV and thermal stresses in corals and human cells

Courtial

Picco

Grover

et al. 2017

Sci Rep

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“…Both roles are exchangeable among eukaryotes 1011 and based on dual-function Urm1-like proteins in archaea and bacteria 1213, conserved Urm1 systems appear to be important in all domains of life. In line with this, their inactivation triggers stress-induced growth defects in microbes, organ underdevelopment in plants and, strikingly, lethality in flies 348121314151617.…”

Section: Introductionmentioning

confidence: 78%

“…Probably, this may help to adapt to conditions known to be URM1 pathway related, i.e. ROS, thermo-stress, S-depletion 6111738394041. However, with attachment of ubiquitin-like modifiers such as SUMO regulating the activity of their targets in ways different from Urm1 2484950, how precisely urmylation impacts on its targets is still not clear.…”

Section: Discussionmentioning

confidence: 99%

“…Together with evidence that reactive oxygen species (ROS) and diamide induce urmylation in yeast and human cells, the S-carrier and protein modifier functions of Urm1 were proposed to be coupled to each other linking both to oxidative stress 461137. In support of this is the evidence showing that ROS detoxifying peroxiredoxins are urmylated in yeast (Ahp1) and fruit flies (Prx5) 461117.…”

Section: Introductionmentioning

confidence: 94%

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Sulfur transfer and activation by ubiquitin-like modifier system Uba4•Urm1 link protein urmylation and tRNA thiolation in yeast

et al. 2016

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Urm1 is a unique dual-function member of the ubiquitin protein family and conserved from yeast to man. It acts both as a protein modifier in ubiquitin-like urmylation and as a sulfur donor for tRNA thiolation, which in concert with the Elongator pathway forms 5-methoxy-carbonyl-methyl-2-thio (mcm5s2) modified wobble uridines (U34) in anticodons. Using Saccharomyces cerevisiae as a model to study a relationship between these two functions, we examined whether cultivation temperature and sulfur supply previously implicated in the tRNA thiolation branch of the URM1 pathway also contribute to proper urmylation. Monitoring Urm1 conjugation, we found urmylation of the peroxiredoxin Ahp1 is suppressed either at elevated cultivation temperatures or under sulfur starvation. In line with this, mutants with sulfur transfer defects that are linked to enzymes (Tum1, Uba4) required for Urm1 activation by thiocarboxylation (Urm1-COSH) were found to maintain drastically reduced levels of Ahp1 urmylation and mcm5s2U34 modification. Moreover, as revealed by site specific mutagenesis, the S-transfer rhodanese domain (RHD) in the E1-like activator (Uba4) crucial for Urm1-COSH formation is critical but not essential for protein urmylation and tRNA thiolation. In sum, sulfur supply, transfer and activation chemically link protein urmylation and tRNA thiolation. These are features that distinguish the ubiquitin-like modifier system Uba4•Urm1 from canonical ubiquitin family members and will help elucidate whether, in addition to their mechanistic links, the protein and tRNA modification branches of the URM1 pathway may also relate in function to one another.

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“…A role of Urm1 in oxidative stress has strongly been supported by the observation of increased levels of urmylation and altered sensitivity during oxidative stress in multiple model systems, including yeast, mammalian cells and in D . melanogaster [ 17 , 19 , 29 ]. However, the attempts to identify Urm1 targets and understand the biological role of target protein urmylation during these processes have been sparse.…”

Section: Introductionmentioning

confidence: 99%

A proteomics approach to identify targets of the ubiquitin-like molecule Urm1 in Drosophila melanogaster

2017

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By covalently conjugating to target proteins, ubiquitin-like modifiers (UBLs) act as important regulators of target protein localization and activity, thereby playing a critical role in the orchestration of cellular biology. The most ancient and one of the least studied UBLs is Urm1, a dual-function protein that in parallel to performing similar functions as its prokaryotic ancestors in tRNA modification, also has adopted the capacity to conjugate to cellular proteins analogous to ubiquitin and other UBL modifiers. In order to increase the understanding of Urm1 and its role in multicellular organisms, we have used affinity purification followed by mass spectrometry to identify putative targets of Urm1 conjugation (urmylation) at three developmental stages of the Drosophila melanogaster lifecycle. Altogether we have recovered 79 Urm1-interacting proteins in Drosophila, which include the already established Urm1 binding partners Prx5 and Uba4, together with 77 candidate urmylation targets that are completely novel in the fly. Among these, the majority was exclusively identified during either embryogenesis, larval stages or in adult flies. We further present biochemical evidence that four of these proteins are covalently conjugated by Urm1, whereas the fifth verified Urm1-binding protein appears to interact with Urm1 via non-covalent means. Besides recapitulating the previously established roles of Urm1 in tRNA modification and during oxidative stress, functional clustering of the newly identified Urm1-associated proteins further positions Urm1 in protein networks that control other types of cellular stress, such as immunological threats and DNA damage. In addition, the functional characteristics of several of the candidate targets strongly match the phenotypes displayed by Urm1n123 null animals, including embryonic lethality, reduced fertility and shortened lifespan. In conclusion, this identification of candidate targets of urmylation significantly increases the knowledge of Urm1 and presents an excellent starting point for unravelling the role of Urm1 in the context of a complex living organism.

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Urm1: an essential regulator of JNK signaling and oxidative stress in Drosophila melanogaster

Cited by 26 publications

References 70 publications

The c-Jun N-terminal kinase prevents oxidative stress induced by UV and thermal stresses in corals and human cells

The c-Jun N-terminal kinase prevents oxidative stress induced by UV and thermal stresses in corals and human cells

Sulfur transfer and activation by ubiquitin-like modifier system Uba4•Urm1 link protein urmylation and tRNA thiolation in yeast

A proteomics approach to identify targets of the ubiquitin-like molecule Urm1 in Drosophila melanogaster

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