Peroxisomal Translocation of Soluble Epoxide Hydrolase Protects against Ischemic Stroke Injury

Nelson, Jonathan W.; Zhang, Wenri; Alkayed, Nabil J.; Koerner, Ines P.

doi:10.1038/jcbfm.2015.159

Cited by 7 publications

(9 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Compartmentalization within specific organelles may similarly be important to EH function. For example, the peroxisomal sEH has been suggested to have a different role than the cytosolic sEH [ 42 ]. Future experiments on cultured cells or whole isolated tissues, where cell and tissue structure are preserved, may serve as a bridge between the in vitro observations in tissue homogenates and translation to human subjects.…”

Section: Discussionmentioning

confidence: 99%

Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues

Morisseau

Kodani

Kamita

et al. 2021

IJMS

View full text Add to dashboard Cite

Epoxy-fatty acids (EpFAs) are endogenous lipid mediators that have a large breadth of biological activities, including the regulation of blood pressure, inflammation, angiogenesis, and pain perception. For the past 20 years, soluble epoxide hydrolase (sEH) has been recognized as the primary enzyme for degrading EpFAs in vivo. The sEH converts EpFAs to the generally less biologically active 1,2-diols, which are quickly eliminated from the body. Thus, inhibitors of sEH are being developed as potential drug therapeutics for various diseases including neuropathic pain. Recent findings suggest that other epoxide hydrolases (EHs) such as microsomal epoxide hydrolase (mEH) and epoxide hydrolase-3 (EH3) can contribute significantly to the in vivo metabolism of EpFAs. In this study, we used two complementary approaches to probe the relative importance of sEH, mEH, and EH3 in 15 human tissue extracts: hydrolysis of 14,15-EET and 13,14-EDP using selective inhibitors and protein quantification. The sEH hydrolyzed the majority of EpFAs in all of the tissues investigated, mEH hydrolyzed a significant portion of EpFAs in several tissues, whereas no significant role in EpFAs metabolism was observed for EH3. Our findings indicate that residual mEH activity could limit the therapeutic efficacy of sEH inhibition in certain organs.

show abstract

Section: Discussionmentioning

confidence: 99%

Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues

Morisseau

Kodani

Kamita

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…This role for sEH would be consistent with the protection from ischemia afforded by R287Q human polymorphism [ 5 , 6 ]. Indeed, the a recent publication has suggested that soluble epoxide hydrolase localized to peroxisomes is protective in ischemia [ 16 ]. This action may be protective through two independent mechanisms; 1) sequestration of the enzyme away from EETs in the cytosol thereby elevating levels of this protective molecule and 2) detoxification of fatty acid epoxides in dysfunctional peroxisomes.…”

Section: Discussionmentioning

confidence: 99%

“…This is an important cell type to understand the mechanism of sEH subcellular distribution given previous studies identifying sEH as a stroke risk factor [ 3 , 13 ]. Furthermore, two mouse studies have suggested that the subcellular distribution of sEH within neurons is linked to the degree of damage in ischemic injury [ 6 , 14 ]. Therefore, we set out to directly test the hypothesis that dimerization regulates the subcellular distribution of sEH in primary neuronal culture.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Disrupting Dimerization Translocates Soluble Epoxide Hydrolase to Peroxisomes

et al. 2016

View full text Add to dashboard Cite

The epoxyeicosatrienoic acid (EET) neutralizing enzyme soluble epoxide hydrolase (sEH) is a neuronal enzyme, which has been localized in both the cytosol and peroxisomes. The molecular basis for its dual localization remains unclear as sEH contains a functional peroxisomal targeting sequence (PTS). Recently, a missense polymorphism was identified in human sEH (R287Q) that enhances its peroxisomal localization. This same polymorphism has also been shown to generate weaker sEH homo-dimers. Taken together, these observations suggest that dimerization may mask the sEH PTS and prevent peroxisome translocation. In the current study, we test the hypothesis that dimerization is a key regulator of sEH subcellular localization. Specifically, we altered the dimerization state of sEH by introducing substitutions in amino acids responsible for the dimer-stabilizing salt-bridge. Green Fluorescent Protein (GFP) fusions of each of mutants were co-transfected into mouse primary cultured cortical neurons together with a PTS-linked red fluorescent protein to constitutively label peroxisomes. Labeled neurons were analyzed using confocal microscopy and co-localization of sEH with peroxisomes was quantified using Pearson’s correlation coefficient. We find that dimer-competent sEH constructs preferentially localize to the cytosol, whereas constructs with weakened or disrupted dimerization were preferentially targeted to peroxisomes. We conclude that the sEH dimerization status is a key regulator of its peroxisomal localization.

show abstract

“…Mammalian sEH is localized to both the cytosol and peroxisomes (Gill, Grant et al, 1994). A previous study indicated sEH contributes to stroke injury only when localized in the cytoplasm, while peroxisomal sEH may be protective, showing the different biological functions of cytosolic and peroxisomal sEH (Nelson, Zhang et al, 2015). Interestingly, the human sEH is located in both cytosolic and peroxisomal compartments in hepatocytes and renal proximal tubules, while sEH is exclusively located in cytosolic compartment in other sEH-containing tissues such as pancreatic islet cells, intestinal epithelium, and anterior pituitary cells.…”

Section: Introductionmentioning

confidence: 99%

PROTAC-mediated selective degradation of cytosolic soluble epoxide hydrolase enhances ER-stress reduction

Wang

Morisseau

Takamura

et al. 2022

Preprint

View full text Add to dashboard Cite

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme responsible for lipid metabolism and is a promising drug target. Here, we report the first-in-class PROTACs small-molecule degraders of sEH. Our optimized PROTAC selectively targets the degradation of cytosolic but not peroxisomal sEH, resulting in exquisite spatiotemporal control. In comparison to the parent sEH inhibitor, sEH-directed PROTAC has higher potency in cellular assays, as measured by significantly reduced ER stress. Surprisingly, PROTAC directs degradation of cytosolic sEH via the lysosome, not through the proteasome, representing the first example of an intracellular lysosomal-dependent PROTAC. The molecules presented here are useful chemical probes to study the biology of sEH with the potential for therapeutic development. Broadly, our results represent a proof-of-concept for the subcellular compartment-selective modulation of a protein class by PROTACs, as well as assisting in the establishment of the cellular mechanism of PROTACs that preferentially direct target proteins for lysosomal degradation.

show abstract

Peroxisomal Translocation of Soluble Epoxide Hydrolase Protects against Ischemic Stroke Injury

Cited by 7 publications

References 16 publications

Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues

Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues

Disrupting Dimerization Translocates Soluble Epoxide Hydrolase to Peroxisomes

PROTAC-mediated selective degradation of cytosolic soluble epoxide hydrolase enhances ER-stress reduction

Contact Info

Product

Resources

About