Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Abul Arif is active.

Publication


Featured researches published by Abul Arif.


Cell | 2014

Target-Selective Protein S-Nitrosylation by Sequence Motif Recognition

Jie Jia; Abul Arif; Fulvia Terenzi; Belinda Willard; Edward F. Plow; Stanley L. Hazen; Paul L. Fox

S-nitrosylation is a ubiquitous protein modification emerging as a principal mechanism of nitric oxide (NO)-mediated signal transduction and cell function. S-nitrosylases can use NO synthase (NOS)-derived NO to modify selected cysteines in target proteins. Despite proteomic identification of over a thousand S-nitrosylated proteins, few S-nitrosylases have been identified. Moreover, mechanisms underlying site-selective S-nitrosylation and the potential role of specific sequence motifs remain largely unknown. Here, we describe a stimulus-inducible, heterotrimeric S-nitrosylase complex consisting of inducible NOS (iNOS), S100A8, and S100A9. S100A9 exhibits transnitrosylase activity, shuttling NO from iNOS to the target protein, whereas S100A8 and S100A9 coordinately direct site selection. A family of proteins S-nitrosylated by iNOS-S100A8/A9 were revealed by proteomic analysis. A conserved I/L-X-C-X2-D/E motif was necessary and sufficient for iNOS-S100A8/A9-mediated S-nitrosylation. These results reveal an elusive parallel between protein S-nitrosylation and phosphorylation, namely, stimulus-dependent posttranslational modification of selected targets by primary sequence motif recognition.


Proceedings of the National Academy of Sciences of the United States of America | 2011

Phosphorylation of glutamyl-prolyl tRNA synthetase by cyclin-dependent kinase 5 dictates transcript-selective translational control

Abul Arif; Jie Jia; Robyn A. Moodt; Paul E. DiCorleto; Paul L. Fox

Cyclin-dependent kinase 5 (Cdk5) is an atypical but essential member of the Cdk kinase family, and its dysregulation or deletion has been implicated in inflammation-related disorders by an undefined mechanism. Here we show that Cdk5 is an indispensable activator of the GAIT (IFN-γ–activated inhibitor of translation) pathway, which suppresses expression of a posttranscriptional regulon of proinflammatory genes in myeloid cells. Through induction of its regulatory protein, Cdk5R1 (p35), IFN-γ activates Cdk5 to phosphorylate Ser886 in the linker domain of glutamyl-prolyl tRNA synthetase (EPRS), the initial event in assembly of the GAIT complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of Ser999, the second essential event in GAIT pathway activation. Diphosphorylated EPRS is released from its residence in the tRNA multisynthetase complex for immediate binding to NS1-associated protein and subsequent binding to ribosomal protein L13a and GAPDH. The mature heterotetrameric GAIT complex binds the 3′ UTR GAIT element of VEGF-A and other target mRNAs and suppresses their translation in myeloid cells. Inhibition of Cdk5/p35 inhibits both EPRS phosphorylation events, prevents EPRS release from the tRNA multisynthetase complex, and blocks translational suppression of GAIT element–bearing mRNAs, resulting in increased expression of inflammatory proteins. Our study reveals a unique role of Cdk5/p35 in activation of the major noncanonical function of EPRS, namely translational control of macrophage inflammatory gene expression.


Molecular and Cellular Biology | 2012

Heterotrimeric GAIT Complex Drives Transcript-Selective Translation Inhibition in Murine Macrophages

Abul Arif; Piyali Chatterjee; Robyn A. Moodt; Paul L. Fox

ABSTRACT The gamma interferon (IFN-γ)-activated inhibitor of translation (GAIT) complex in human myeloid cells is heterotetrameric, consisting of glutamyl-prolyl-tRNA synthetase (EPRS), NS1-associated protein 1 (NSAP1), ribosomal protein L13a, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The complex binds a structural GAIT element in the 3′ untranslated region of VEGF-A and other inflammation-related transcripts and inhibits their translation. EPRS is dually phosphorylated by cyclin-dependent kinase 5 (Cdk5) at Ser886 and then by a Cdk5-dependent-AGC kinase at Ser999; L13a is phosphorylated at Ser77 by death-associated protein kinases DAPK and ZIPK. Because profound differences in inflammatory responses between mice and humans are known, we investigated the GAIT system in mouse macrophages. The murine GAIT complex is heterotrimeric, lacking NSAP1. As in humans, IFN-γ activates the mouse macrophage GAIT system via induced phosphorylation of EPRS and L13a. Murine L13a is phosphorylated at Ser77 by the DAPK-ZIPK cascade, but EPRS is phosphorylated only at Ser999. Loss of EPRS Ser886 phosphorylation prevents NSAP1 incorporation into the GAIT complex. However, the triad of Ser999-phosphorylated EPRS, Ser77-phosphorylated L13a, and GAPDH forms a functional GAIT complex that inhibits translation of GAIT target mRNAs. Thus, translational control by the heterotrimeric GAIT complex in mice exemplifies the distinctive species-specific responses of myeloid cells to inflammatory stimuli.


Nature | 2017

EPRS is a critical mTORC1–S6K1 effector that influences adiposity in mice

Abul Arif; Fulvia Terenzi; Alka A. Potdar; Jie Jia; Jessica Sacks; Arnab China; Dalia Halawani; Kommireddy Vasu; Xiaoxia Li; J. Mark Brown; Jie Chen; Sara C. Kozma; George Thomas; Paul L. Fox

Metabolic pathways that contribute to adiposity and ageing are activated by the mammalian target of rapamycin complex 1 (mTORC1) and p70 ribosomal protein S6 kinase 1 (S6K1) axis. However, known mTORC1–S6K1 targets do not account for observed loss-of-function phenotypes, suggesting that there are additional downstream effectors of this pathway. Here we identify glutamyl-prolyl-tRNA synthetase (EPRS) as an mTORC1–S6K1 target that contributes to adiposity and ageing. Phosphorylation of EPRS at Ser999 by mTORC1–S6K1 induces its release from the aminoacyl tRNA multisynthetase complex, which is required for execution of noncanonical functions of EPRS beyond protein synthesis. To investigate the physiological function of EPRS phosphorylation, we generated Eprs knock-in mice bearing phospho-deficient Ser999-to-Ala (S999A) and phospho-mimetic (S999D) mutations. Homozygous S999A mice exhibited low body weight, reduced adipose tissue mass, and increased lifespan, similar to S6K1-deficient mice and mice with adipocyte-specific deficiency of raptor, an mTORC1 constituent. Substitution of the EprsS999D allele in S6K1-deficient mice normalized body mass and adiposity, indicating that EPRS phosphorylation mediates S6K1-dependent metabolic responses. In adipocytes, insulin stimulated S6K1-dependent EPRS phosphorylation and release from the multisynthetase complex. Interaction screening revealed that phospho-EPRS binds SLC27A1 (that is, fatty acid transport protein 1, FATP1), inducing its translocation to the plasma membrane and long-chain fatty acid uptake. Thus, EPRS and FATP1 are terminal mTORC1–S6K1 axis effectors that are critical for metabolic phenotypes.


Nature Immunology | 2016

Infection-specific phosphorylation of glutamyl-prolyl tRNA synthetase induces antiviral immunity

Eun-Young Lee; Hyun Cheol Lee; Hyun Kwan Kim; Song Yee Jang; Seong Jun Park; Yong Hoon Kim; Jong Hwan Kim; Jungwon Hwang; Jae Hoon Kim; Tae-Hwan Kim; Abul Arif; Seon Young Kim; Young Ki Choi; Cheolju Lee; Chul Ho Lee; Jae U. Jung; Paul L. Fox; Sunghoon Kim; Jong-Soo Lee; Myung Hee Kim

The mammalian cytoplasmic multi-tRNA synthetase complex (MSC) is a depot system that regulates non-translational cellular functions. Here we found that the MSC component glutamyl-prolyl-tRNA synthetase (EPRS) switched its function following viral infection and exhibited potent antiviral activity. Infection-specific phosphorylation of EPRS at Ser990 induced its dissociation from the MSC, after which it was guided to the antiviral signaling pathway, where it interacted with PCBP2, a negative regulator of mitochondrial antiviral signaling protein (MAVS) that is critical for antiviral immunity. This interaction blocked PCBP2-mediated ubiquitination of MAVS and ultimately suppressed viral replication. EPRS-haploid (Eprs+/−) mice showed enhanced viremia and inflammation and delayed viral clearance. This stimulus-inducible activation of MAVS by EPRS suggests an unexpected role for the MSC as a regulator of immune responses to viral infection.


Comparative Biochemistry and Physiology B | 2010

Identification of a developmentally and hormonally regulated Delta-Class glutathione S-transferase in rice moth Corcyra cephalonica.

Damodar Gullipalli; Abul Arif; Polamarasetty Aparoy; Gavin J. Svenson; Michael F. Whiting; Pallu Reddanna; Aparna Dutta-Gupta

Glutathione S-transferases (GSTs) are a large family of multifunctional enzymes, known for their role in cellular detoxification. Here we report a cytosolic GST with optimal activity at alkaline pH (8.3) from the visceral fat body of late-last instar (LLI) larvae of a lepidopteran insect rice moth Corcyra cephalonica. All previously known GSTs are active between pH 6.0 to 6.5. Purification and characterization revealed the Corcyra cephalonica GST (CcGST) as a 23-kDa protein. HPLC and 2D analysis showed a single isoform of the protein in the LLI visceral fat body. Degenerate primer based method identified a 701-nucleotide cDNA and the longest open reading frame contained 216 amino acids. Multiple sequence and structural alignment showed close similarity with delta-class GSTs. CcGST is present mainly in the fat body with highest activity at the late-last instar larval stage. Juvenile hormone (JH) negatively inhibits the CcGST activity both ex vivo and in vivo. We speculate that high expression and activity of CcGST in the fat body of the late-last instar larvae, when endogenous JH titer is low may have role in the insect post-embryonic development unrelated to their previously known function.


Insect Biochemistry and Molecular Biology | 2008

Regulation of hexamerin receptor phosphorylation by hemolymph protein HP19 and 20-hydroxyecdysone directs hexamerin uptake in the rice moth Corcyra cephalonica

Abul Arif; Damara Manohar; Damodar Gullipalli; Aparna Dutta-Gupta

Hexamerins are stage specifically sequestered during the non-feeding stages mainly by the fat body cells from hemolymph through ecdysteroid regulated receptor-mediated endocytosis. 20-Hydroxyecdysone (20E) stimulates the tyrosine kinase-mediated phosphorylation of the 120kDa hexamerin receptor in the rice moth, Corcyra cephalonica. Here, we demonstrate that phosphorylation of the hexamerin receptor by HP19-regulated-20E-dependent-tyrosine kinase is a critical regulator for its activation, and is required for hexamerin uptake. Hexamerin receptor is phosphorylated only in the hexamerin sequestering tissues. The receptor phosphorylation is a prerequisite for hexamerin uptake and both phosphorylation and concomitant uptake are developmentally regulated. In addition, endogenous fat body tyrosine kinase activity is also developmentally and hormonally regulated. 20E induces the tyrosine kinase activity both in vivo as well as ex vivo, and the receptor phosphorylation is likely an extra-cellular event. The hemolymph protein, HP19 inhibits the 20E-induced phosphorylation by inhibiting tyrosine kinase activity. These inhibitions are rapid in homogenate preparations and are unaffected by the inhibitors of transcription and translation. We propose that hexamerin sequestration is negatively regulated by active HP19 at the feeding larval stage, thus preventing the uptake. During the non-feeding pupal stage, high ecdysteroid titer and negligible HP19 activity, positively regulates the receptor phosphorylation resulting in hexamerin uptake. These studies are therefore the first evidence of hexamerin uptake regulated by the orchestration of 20E and HP19 at a nongenomic level.


Wiley Interdisciplinary Reviews - Rna | 2018

The GAIT translational control system

Abul Arif; Peng Yao; Fulvia Terenzi; Jie Jia; Partho Sarothi Ray; Paul L. Fox

The interferon (IFN)‐γ‐activated inhibitor of translation (GAIT) system directs transcript‐selective translational control of functionally related genes. In myeloid cells, IFN‐γ induces formation of a multiprotein GAIT complex that binds structural GAIT elements in the 3′‐untranslated regions (UTRs) of multiple inflammation‐related mRNAs, including ceruloplasmin and VEGF‐A, and represses their translation. The human GAIT complex is a heterotetramer containing glutamyl‐prolyl tRNA synthetase (EPRS), NS1‐associated protein 1 (NSAP1), ribosomal protein L13a (L13a), and glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH). A network of IFN‐γ‐stimulated kinases regulates recruitment and assembly of GAIT complex constituents. Activation of cyclin‐dependent kinase 5 (Cdk5), mammalian target of rapamycin complex 1 (mTORC1), and S6K1 kinases induces EPRS release from its parental multiaminoacyl tRNA synthetase complex to join NSAP1 in a ‘pre‐GAIT’ complex. Subsequently, the DAPK‐ZIPK kinase axis phosphorylates L13a, inducing release from the 60S ribosomal subunit and binding to GAPDH. The subcomplexes join to form the functional GAIT complex. Each constituent has a distinct role in the GAIT system. EPRS binds the GAIT element in target mRNAs, NSAP1 negatively regulates mRNA binding, L13a binds eIF4G to block ribosome recruitment, and GAPDH shields L13a from proteasomal degradation. The GAIT system is susceptible to genetic and condition‐specific regulation. An N‐terminus EPRS truncate is a dominant‐negative inhibitor ensuring a ‘translational trickle’ of target transcripts. Also, hypoxia and oxidatively modified lipoproteins regulate GAIT activity. Mouse models exhibiting absent or genetically modified GAIT complex constituents are beginning to elucidate the physiological role of the GAIT system, particularly in the resolution of chronic inflammation. Finally, GAIT‐like systems in proto‐chordates suggests an evolutionarily conserved role of the pathway in innate immunity. WIREs RNA 2018, 9:e1441. doi: 10.1002/wrna.1441


Methods | 2017

Experimental approaches for investigation of aminoacyl tRNA synthetase phosphorylation

Abul Arif; Jie Jia; Dalia Halawani; Paul L. Fox

Phosphorylation of many aminoacyl tRNA synthetases (AARSs) has been recognized for decades, but the contribution of post-translational modification to their primary role in tRNA charging and decryption of genetic code remains unclear. In contrast, phosphorylation is essential for performance of diverse noncanonical functions of AARSs unrelated to protein synthesis. Phosphorylation of glutamyl-prolyl tRNA synthetase (EPRS) has been investigated extensively in our laboratory for more than a decade, and has served as an archetype for studies of other AARSs. EPRS is a constituent of the IFN-γ-activated inhibitor of translation (GAIT) complex that directs transcript-selective translational control in myeloid cells. Stimulus-dependent phosphorylation of EPRS is essential for its release from the parental multi-aminoacyl tRNA synthetase complex (MSC), for binding to other GAIT complex proteins, and for regulating the binding to target mRNAs. Importantly, phosphorylation is the common driving force for the context- and stimulus-dependent release, and non-canonical activity, of other AARSs residing in the MSC, for example, lysyl tRNA synthetase (KARS). Here, we describe the concepts and experimental methodologies we have used to investigate the influence of phosphorylation on the structure and function of EPRS. We suggest that application of these approaches will help to identify new functional phosphorylation event(s) in other AARSs and elucidate their possible roles in noncanonical activities.


Journal of Biological Chemistry | 2018

Structural control of caspase-generated glutamyl-tRNA synthetase by appended noncatalytic WHEP domains

Dalia Halawani; Valentin Gogonea; Joseph A. DiDonato; Vitaliy Pipich; Peng Yao; Arnab China; Celalettin Topbas; Kommireddy Vasu; Abul Arif; Stanley L. Hazen; Paul L. Fox

Aminoacyl-tRNA synthetases are ubiquitous, evolutionarily conserved enzymes catalyzing the conjugation of amino acids onto cognate tRNAs. During eukaryotic evolution, tRNA synthetases have been the targets of persistent structural modifications. These modifications can be additive, as in the evolutionary acquisition of noncatalytic domains, or subtractive, as in the generation of truncated variants through regulated mechanisms such as proteolytic processing, alternative splicing, or coding region polyadenylation. A unique variant is the human glutamyl-prolyl-tRNA synthetase (EPRS) consisting of two fused synthetases joined by a linker containing three copies of the WHEP domain (termed by its presence in tryptophanyl-, histidyl-, and glutamyl-prolyl-tRNA synthetases). Here, we identify site-selective proteolysis as a mechanism that severs the linkage between the EPRS synthetases in vitro and in vivo. Caspase action targeted Asp-929 in the third WHEP domain, thereby separating the two synthetases. Using a neoepitope antibody directed against the newly exposed C terminus, we demonstrate EPRS cleavage at Asp-929 in vitro and in vivo. Biochemical and biophysical characterizations of the N-terminally generated EPRS proteoform containing the glutamyl-tRNA synthetase and most of the linker, including two WHEP domains, combined with structural analysis by small-angle neutron scattering, revealed a role for the WHEP domains in modulating conformations of the catalytic core and GSH–S-transferase–C-terminal-like (GST-C) domain. WHEP-driven conformational rearrangement altered GST–C domain interactions and conferred distinct oligomeric states in solution. Collectively, our results reveal long-range conformational changes imposed by the WHEP domains and illustrate how noncatalytic domains can modulate the global structure of tRNA synthetases in complex eukaryotic systems.

Collaboration


Dive into the Abul Arif's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge