Peptidylarginine deiminases and extracellular vesicles: prospective drug targets and biomarkers in central nervous system diseases and repair

Peptidylarginine deiminases are a family of calcium-activated enzymes with multifaceted roles in physiological and pathological processes,including in the central nervous system.Peptidylarginine deiminases cause post-translational deimination/citrullination,leading to changes in structure and function of a wide range of target proteins.Deimination can facilitate protein moonlighting,modify protein-protein interaction,cause protein dysfunction and induce inflammatory responses.Peptidylarginine deiminases also regulate the biogenesis of extracellular vesicles,which play important roles in cellular communication through transfer of extracellular vesicle-cargo,e.g.,proteins and genetic material.Both peptidylarginine deiminases and extracellular vesicles are linked to a number of pathologies,including in the central nervous system,and their modulation with pharmacological peptidylarginine deiminase inhibitors have shown great promise in several in vitro and in vivo central nervous system disease models.Furthermore,extracellular vesicles derived from mesenchymal stem cells have been assessed for their therapeutic application in central nervous system injury.As circulating extracellular vesicles can be used as non-invasive liquid biopsies,their specific cargo-signatures(including deiminated proteins and microRNAs)may allow for disease“fingerprinting”and aid early central nervous system disease diagnosis,inform disease progression and response to therapy.This mini-review discusses recent advances in the field of peptidylarginine deiminase and extracellular vesicle research in the central nervous system,focusing on several central nervous system acute injury,degeneration and cancer models.

Nematode-induced trap formation regulated by the histone H3K4 methyltransferase AoSET1 in the nematode-trapping fungus Arthrobotrys oligospora

The methylation of lysine 4 of histone H3(H3K4),catalyzed by the histone methyltransferase KMT2/SET1,has been functionally identified in many pathogenic fungi but remains unexplored in nematode-trapping fungi(NTFs).Here,we report a regulatory mechanism of an H3K4-specific SET1 orthologue,AoSET1,in the typical nematode-trapping fungus Arthrobotrys oligospora.When the fungus is induced by the nematode,the expression of AoSET1 is up-regulated.Disruption of AoSet1 led to the abolishment of H3K4me.Consequently,the yield of traps and conidia ofΔAoSet1 was significantly lower than that of the WT strain,and the growth rate and pathogenicity were also compromised.Moreover,H3K4 trimethylation was enriched mainly in the promoter of two bZip transcription factor genes(AobZip129 and AobZip350)and ultimately up-regulated the expression level of these two transcription factor genes.In theΔAoSet1 and AoH3K4A strains,the H3^(K4)me modification level was significantly decreased at the promoter of transcription factor genes AobZip129 and AobZip350.These results suggest that AoSET1-mediated H3KEme serves as an epigenetic marker of the promoter region of the targeted transcription factor genes.Furthermore,we found that AobZip129 negatively regulates the formation of adhesive networks and the pathogenicity of downstream AoPABP1 and AoCPR1.Our findings confirm that the epigenetic regulatory mechanism plays a pivotal role in regulating trap formation and pathogenesis in NTFs,and provide novel insights into the mechanisms of interaction between NTFs and nematodes.

PKC-SWI6 signaling regulates asexual development,cell wall integrity,stress response,and lifestyle transition in the nematode-trapping fungus Arthrobotrys oligospora

Predatory fungi possess intricate signal transduction systems that regulate their development and support successful infection of the host.Herein,we characterized three components of the cell wall integrity-controlling pathway,namely protein kinase C(Ao PKC),SLT2-MAPK(Ao SLT2),and SWI6(Ao SWI6),in a representative nematode-trapping fungus Arthrobotrys oligospora,using gene disruption and multi-omics approaches.The phenotypic traits(such as mycelia development,conidiation,stress response,and trap morphogenesis) and metabolic profiles of ΔAopkc and ΔAoswi6 mutants were similar but differed from those of the ΔAoslt2 mutants.Transcriptomic analysis indicated that the genes differentially expressed in the absence of Aoswi6 were involved in DNA replication,repair,and recombination during trap formation.Moreover,the yeast two-hybrid assay showed that Ao PKC interacted with Ao SWI6,suggesting that in A.oligospora,PKC can directly regulate SWI6,bypassing the SLT2signaling cascade.Conclusively,our findings deepen our understanding of the regulatory mechanism of asexual development and lifestyle switching in nematode-trapping fungi.