36 results found
Sanchez-Garrido J, Sancho-Shimizu V, Shenoy AR, 2018, Regulated proteolysis of p62/SQSTM1 enables differential control of autophagy and nutrient sensing., Sci Signal, Vol: 11
The multidomain scaffold protein p62 (also called sequestosome-1) is involved in autophagy, antimicrobial immunity, and oncogenesis. Mutations in SQSTM1, which encodes p62, are linked to hereditary inflammatory conditions such as Paget's disease of the bone, frontotemporal dementia (FTD), amyotrophic lateral sclerosis, and distal myopathy with rimmed vacuoles. Here, we report that p62 was proteolytically trimmed by the protease caspase-8 into a stable protein, which we called p62TRM We found that p62TRM, but not full-length p62, was involved in nutrient sensing and homeostasis through the mechanistic target of rapamycin complex 1 (mTORC1). The kinase RIPK1 and caspase-8 controlled p62TRM production and thus promoted mTORC1 signaling. An FTD-linked p62 D329G polymorphism and a rare D329H variant could not be proteolyzed by caspase-8, and these noncleavable variants failed to activate mTORC1, thereby revealing the detrimental effect of these mutations. These findings on the role of p62TRM provide new insights into SQSTM1-linked diseases and mTORC1 signaling.
Ahmad L, Mashbat B, Leung C, et al., 2018, Human TANK-binding kinase 1 is required for early autophagy induction upon herpes simplex virus 1 infection., J Allergy Clin Immunol
Shenoy AR, Furniss RCD, Goddard PJ, et al., 2018, Modulation of Host Cell Processes by T3SS Effectors, ESCHERICHIA COLI, A VERSATILE PATHOGEN, Editors: Frankel, Ron, Publisher: SPRINGER INTERNATIONAL PUBLISHING AG, Pages: 73-115, ISBN: 978-3-319-99663-9
Bist P, Cheong WS, Ng A, et al., 2017, E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP, NATURE COMMUNICATIONS, Vol: 8, ISSN: 2041-1723
Mazon-Moya MJ, Willis AR, Torraca V, et al., 2017, Septins restrict inflammation and protect zebrafish larvae from Shigella infection, PLOS PATHOGENS, Vol: 13, ISSN: 1553-7366
Pallett MA, Crepin VF, Serafini N, et al., 2017, Bacterial virulence factor inhibits caspase-4/11 activation in intestinal epithelial cells, MUCOSAL IMMUNOLOGY, Vol: 10, Pages: 602-612, ISSN: 1933-0219
Eldridge MJG, Sanchez-Garrido J, Hoben GF, et al., 2017, The Atypical Ubiquitin E2 Conjugase UBE2L3 Is an Indirect Caspase-1 Target and Controls IL-1 beta Secretion by Inflammasomes, CELL REPORTS, Vol: 18, Pages: 1285-1297, ISSN: 2211-1247
Thurston TLM, Matthews SA, Jennings E, et al., 2016, Growth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death, NATURE COMMUNICATIONS, Vol: 7, ISSN: 2041-1723
Surana S, Shenoy AR, Krishnan Y, 2015, Designing DNA nanodevices for compatibility with the immune system of higher organisms, NATURE NANOTECHNOLOGY, Vol: 10, Pages: 741-747, ISSN: 1748-3387
Mostowy S, Shenoy AR, 2015, The cytoskeleton in cell-autonomous immunity: structural determinants of host defence, NATURE REVIEWS IMMUNOLOGY, Vol: 15, Pages: 559-573, ISSN: 1474-1733
Eldridge MJG, Shenoy AR, 2015, Antimicrobial inflammasomes: unified signalling against diverse bacterial pathogens, CURRENT OPINION IN MICROBIOLOGY, Vol: 23, Pages: 32-41, ISSN: 1369-5274
Matsuzawa T, Kim B-H, Shenoy AR, et al., 2012, IFN-γ elicits macrophage autophagy via the p38 MAPK signaling pathway., J Immunol, Vol: 189, Pages: 813-818
Autophagy is a major innate immune defense pathway in both plants and animals. In mammals, this cascade can be elicited by cytokines (IFN-γ) or pattern recognition receptors (TLRs and nucleotide-binding oligomerization domain-like receptors). Many signaling components in TLR- and nucleotide-binding oligomerization domain-like receptor-induced autophagy are now known; however, those involved in activating autophagy via IFN-γ remain to be elucidated. In this study, we engineered macrophages encoding a tandem fluorescently tagged LC3b (tfLC3) autophagosome reporter along with stably integrated short hairpin RNAs to demonstrate IFN-γ-induced autophagy required JAK 1/2, PI3K, and p38 MAPK but not STAT1. Moreover, the autophagy-related guanosine triphosphatase Irgm1 proved dispensable in both stable tfLC3-expressing RAW 264.7 and tfLC3-transduced Irgm1(-/-) primary macrophages, revealing a novel p38 MAPK-dependent, STAT1-independent autophagy pathway that bypasses Irgm1. These unexpected findings have implications for understanding how IFN-γ-induced autophagy is mobilized within macrophages for inflammation and host defense.
Shenoy AR, Wellington DA, Kumar P, et al., 2012, GBP5 Promotes NLRP3 Inflammasome Assembly and Immunity in Mammals, SCIENCE, Vol: 336, Pages: 481-485, ISSN: 0036-8075
Kim B-H, Shenoy AR, Kumar P, et al., 2011, A family of IFN-γ-inducible 65-kD GTPases protects against bacterial infection., Science, Vol: 332, Pages: 717-721
Immune interferon gamma (IFN-γ) is essential for mammalian host defense against intracellular pathogens. IFN-γ induces nearly 2000 host genes, yet few have any assigned function. Here, we examined a complete mouse 65-kilodalton (kD) guanylate-binding protein (Gbp) gene family as part of a 43-member IFN-γ-inducible guanosine triphosphatase (GTPase) superfamily in mouse and human genomes. Family-wide loss-of-function analysis found that at least four Gbps--Gbp1, Gbp6, Gbp7, and Gbp10--conferred cell-autonomous immunity to listerial or mycobacterial infection within macrophages and gene-deficient animals. These Gbps solicited host defense proteins, including the phagocyte oxidase, antimicrobial peptides, and autophagy effectors, to kill intracellular bacteria. Thus, specific 65-kD Gbps coordinate a potent oxidative and vesicular trafficking program to protect the host from infection.
Biswas KH, Shenoy AR, Dutta A, et al., 2009, The Evolution of Guanylyl Cyclases as Multidomain Proteins: Conserved Features of Kinase-Cyclase Domain Fusions, JOURNAL OF MOLECULAR EVOLUTION, Vol: 68, Pages: 587-602, ISSN: 0022-2844
Tyagi R, Shenoy AR, Visweswariah SS, 2009, Characterization of an Evolutionarily Conserved Metallophosphoesterase That Is Expressed in the Fetal Brain and Associated with the WAGR Syndrome, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 284, Pages: 5217-5228, ISSN: 0021-9258
Dass BKM, Sharma R, Shenoy AR, et al., 2008, Cyclic AMP in mycobacteria: Characterization and functional role of the rv1647 ortholog in Mycobacterium smegmatis, JOURNAL OF BACTERIOLOGY, Vol: 190, Pages: 3824-3834, ISSN: 0021-9193
Shenoy AR, Capuder M, Draskovic P, et al., 2007, Structural and biochemical analysis of the Rv0805 cyclic nucleotide phosphodiesterase from Mycobacterium tuberculosis, JOURNAL OF MOLECULAR BIOLOGY, Vol: 365, Pages: 211-225, ISSN: 0022-2836
Shenoy AR, Kim B-H, Choi H-P, et al., 2007, Emerging themes in IFN-gamma-induced macrophage immunity by the p47 and p65 GTPase families, IMMUNOBIOLOGY, Vol: 212, Pages: 771-784, ISSN: 0171-2985
Shenoy AR, Visweswariah SS, 2006, New messages from old messengers: cAMP and mycobacteria, TRENDS IN MICROBIOLOGY, Vol: 14, Pages: 543-550, ISSN: 0966-842X
Macario AJL, Brocchieri L, Shenoy AR, et al., 2006, Evolution of a protein-folding machine: Genomic and evolutionary analyses reveal three lineages of the archaeal hsp70(dnaK) gene, JOURNAL OF MOLECULAR EVOLUTION, Vol: 63, Pages: 74-86, ISSN: 0022-2844
Shenoy AR, Visweswariah SS, 2006, Mycobacterial adenylyl cyclases: Biochemical diversity and structural plasticity, FEBS LETTERS, Vol: 580, Pages: 3344-3352, ISSN: 0014-5793
Ketkar AD, Shenoy AR, Ramagopal UA, et al., 2006, A structural basis for the role of nucleotide specifying residues in regulating the oligomerization of the Rv1625c adenylyl cyclase from M. tuberculosis., J Mol Biol, Vol: 356, Pages: 904-916, ISSN: 0022-2836
The Rv1625c Class III adenylyl cyclase from Mycobacterium tuberculosis is a homodimeric enzyme with two catalytic centers at the dimer interface, and shows sequence similarity with the mammalian adenylyl and guanylyl cyclases. Mutation of the substrate-specifying residues in the catalytic domain of Rv1625c, either independently or together, to those present in guanylyl cyclases not only failed to confer guanylyl cyclase activity to the protein, but also severely abrogated the adenylyl cyclase activity of the enzyme. Biochemical analysis revealed alterations in the behavior of the mutants on ion-exchange chromatography, indicating differences in the surface-exposed charge upon mutation of substrate-specifying residues. The mutant proteins showed alterations in oligomeric status as compared to the wild-type enzyme, and differing abilities to heterodimerize with the wild-type protein. The crystal structure of a mutant has been solved to a resolution of 2.7A. On the basis of the structure, and additional biochemical studies, we provide possible reasons for the altered properties of the mutant proteins, as well as highlight unique structural features of the Rv1625c adenylyl cyclase.
Jaleel M, Saha S, Shenoy AR, et al., 2006, The kinase homology domain of receptor guanylyl cyclase C: ATP binding and identification of an adenine nucleotide sensitive site, BIOCHEMISTRY, Vol: 45, Pages: 1888-1898, ISSN: 0006-2960
Shenoy AR, Sreenath N, Podobnik M, et al., 2005, The Rv0805 gene from Mycobacterium tuberculosis encodes a 3 ',5 '-cyclic nucleotide phosphodiesterase: Biochemical and mutational analysis, BIOCHEMISTRY, Vol: 44, Pages: 15695-15704, ISSN: 0006-2960
Shenoy AR, Srinivas A, Mahalingam M, et al., 2005, An adenylyl cyclase pseudogene in Mycobacterium tuberculosis has a functional ortholog in Mycobacterium avium, BIOCHIMIE, Vol: 87, Pages: 557-563, ISSN: 0300-9084
Shenoy AR, Sreenath NP, Mahalingam M, et al., 2005, Characterization of phylogenetically distant members of the adenylate cyclase family from mycobacteria: Rv1647 from Mycobacterium tuberculosis and its orthologue ML1399 from M. leprae, BIOCHEMICAL JOURNAL, Vol: 387, Pages: 541-551, ISSN: 0264-6021
Jaleel M, Shenoy AR, Visweswariah SS, 2004, Tyrphostins are inhibitors of guanylyl and adenylyl cyclases, BIOCHEMISTRY, Vol: 43, Pages: 8247-8255, ISSN: 0006-2960
Shenoy AR, Visweswariah SS, 2004, Class III nucleotide cyclases in bacteria and archaebacteria: lineage-specific expansion of adenylyl cyclases and a dearth of guanylyl cyclases, FEBS LETTERS, Vol: 561, Pages: 11-21, ISSN: 0014-5793
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