SUMOylation of Arginyl tRNA Synthetase Modulates the Drosophila Innate Immune Response

SUMO conjugation of a substrate protein can modify its activity, localization, interaction or function. A large number of SUMO targets in cells have been identified by Proteomics, but biological roles for SUMO conjugation for most targets remains elusive. The multi-aminoacyl tRNA synthetase complex (MARS) is a sensor and regulator of immune signaling. The proteins of this 1.2 MDa complex are targets of SUMO conjugation, in response to infection. Arginyl tRNA Synthetase (RRS), a member of the sub-complex II of MARS, is one such SUMO conjugation target. The sites for SUMO conjugation are Lys 147 and 383. Replacement of these residues by Arg (RRSK147R,K383R), creates a SUMO conjugation resistant variant (RRSSCR). Transgenic Drosophila lines for RRSWT and RRSSCR were generated by expressing these variants in a RRS loss of function (lof) animal, using the UAS-Gal4 system. The RRS-lof line was itself generated using CRISPR/Cas9 genome editing. Expression of both RRSWT and RRSSCR rescue the RRS-lof lethality. Adult animals expressing RRSWT and RRSSCR are compared and contrasted for their response to bacterial infection by gram positive M. luteus and gram negative Ecc15. We find that RRSSCR, when compared to RRSWT, shows modulation of the transcriptional response, as measured by quantitative 3′ mRNA sequencing. Our study uncovers a possible non-canonical role for SUMOylation of RRS, a member of the MARS complex, in host-defense.

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Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson’s disease

Brain ◽

10.1093/brain/awz172 ◽

2019 ◽

Vol 142 (8) ◽

pp. 2380-2401 ◽

Cited By ~ 9

Author(s):

Saurav Brahmachari ◽

Saebom Lee ◽

Sangjune Kim ◽

Changqing Yuan ◽

Senthilkumar S Karuppagounder ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Zinc Finger ◽

Zinc Finger Protein ◽

Critical Role ◽

Trna Synthetase ◽

Loss Of Function ◽

Substrate Protein ◽

Finger Protein ◽

Sporadic Parkinson’S Disease

Abstract α-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson’s disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson’s disease, there is evidence that parkin is inactivated in sporadic Parkinson’s disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson’s disease or a mere spectator is unknown. Here we show that parkin in inactivated through c-Abelson kinase phosphorylation of parkin in three α-synuclein-induced models of neurodegeneration. This results in the accumulation of parkin interacting substrate protein (zinc finger protein 746) and aminoacyl tRNA synthetase complex interacting multifunctional protein 2 with increased parkin interacting substrate protein levels playing a critical role in α-synuclein-induced neurodegeneration, since knockout of parkin interacting substrate protein attenuates the degenerative process. Thus, accumulation of parkin interacting substrate protein links parkin inactivation and α-synuclein in a common pathogenic neurodegenerative pathway relevant to both sporadic and familial forms Parkinson’s disease. Thus, suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson’s disease and related α-synucleinopathies.

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Compound heterozygosity for loss-of-function FARSB variants in a patient with classic features of recessive aminoacyl-tRNA synthetase-related disease

Human Mutation ◽

10.1002/humu.23424 ◽

2018 ◽

Vol 39 (6) ◽

pp. 834-840 ◽

Cited By ~ 15

Author(s):

Anthony Antonellis ◽

Stephanie N. Oprescu ◽

Laurie B. Griffin ◽

Amer Heider ◽

Andrea Amalfitano ◽

...

Keyword(s):

Trna Synthetase ◽

Compound Heterozygosity ◽

Loss Of Function ◽

Aminoacyl Trna Synthetase ◽

Related Disease

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Loss of Function of Scavenger Receptor SCAV-5 Protects C. elegans Against Pathogenic Bacteria

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.593745 ◽

2021 ◽

Vol 11 ◽

Author(s):

Aixiao Luo ◽

Huiru Jing ◽

Lei Yuan ◽

Yanzhe Wang ◽

Hui Xiao ◽

...

Keyword(s):

Host Defense ◽

Pathogenic Bacteria ◽

Mapk Pathway ◽

Critical Role ◽

Scavenger Receptor ◽

Innate Immune ◽

Scavenger Receptors ◽

Loss Of Function ◽

C Elegans ◽

Class B

Scavenger receptors play a critical role in innate immunity by acting as the pattern-recognition receptors. There are six class B scavenger receptors homologs in C. elegans. However, it remains unclear whether they are required for host defense against bacterial pathogens. Here, we show that, of the six SCAV proteins, only loss of function scav-5 protect C. elegans against pathogenic bacteria S. typhimurium SL1344 and P. aeruginosa PA14 by different mechanism. scav-5 mutants are resistant to S. typhimurium SL1344 due to dietary restriction. While scav-5 acts upstream of or in parallel to tir-1 in conserved PMK-1 p38 MAPK pathway to upregulate the innate immune response to defend worms against P. aeruginosa PA14. This is the first demonstration of a role for SCAV-5 in host defense against pathogenic bacteria. Our results provide an important basis for further elucidating the underlying molecular mechanism by which scav-5 regulates innate immune responses.

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E3 ubiquitin ligases

Essays in Biochemistry ◽

10.1042/bse0410015 ◽

2005 ◽

Vol 41 ◽

pp. 15-30 ◽

Cited By ~ 123

Author(s):

Helen C. Ardley ◽

Philip A. Robinson

Keyword(s):

Protein Complexes ◽

Loss Of Function ◽

Direct Role ◽

Cellular Processes ◽

Substrate Protein ◽

Protein Ubiquitination ◽

C Terminus ◽

Full Complement ◽

Spatio Temporal ◽

Eukaryotic Organisms

The selectivity of the ubiquitin–26 S proteasome system (UPS) for a particular substrate protein relies on the interaction between a ubiquitin-conjugating enzyme (E2, of which a cell contains relatively few) and a ubiquitin–protein ligase (E3, of which there are possibly hundreds). Post-translational modifications of the protein substrate, such as phosphorylation or hydroxylation, are often required prior to its selection. In this way, the precise spatio-temporal targeting and degradation of a given substrate can be achieved. The E3s are a large, diverse group of proteins, characterized by one of several defining motifs. These include a HECT (homologous to E6-associated protein C-terminus), RING (really interesting new gene) or U-box (a modified RING motif without the full complement of Zn2+-binding ligands) domain. Whereas HECT E3s have a direct role in catalysis during ubiquitination, RING and U-box E3s facilitate protein ubiquitination. These latter two E3 types act as adaptor-like molecules. They bring an E2 and a substrate into sufficiently close proximity to promote the substrate's ubiquitination. Although many RING-type E3s, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, can apparently act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex. Taken together, these multifaceted properties and interactions enable E3s to provide a powerful, and specific, mechanism for protein clearance within all cells of eukaryotic organisms. The importance of E3s is highlighted by the number of normal cellular processes they regulate, and the number of diseases associated with their loss of function or inappropriate targeting.

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