Imd pathway

The Imd pathway bears a number of similarities to mammalian TNFR signalling, though many of the intracellular regulatory proteins of Imd signalling also bear homology to different signalling cascades of human Toll-like receptors.

The following genes are analogous or homologous between Drosophila melanogaster (in bold) and human TNFR1 signalling:{{cite journal | vauthors = Myllymäki H, Valanne S, Rämet M | title = The Drosophila imd signaling pathway | journal = Journal of Immunology | volume = 192 | issue = 8 | pages = 3455–3462 | date = April 2014 | pmid = 24706930 | doi = 10.4049/jimmunol.1303309 | doi-access = free }}{{cite web |title=UniProtKB - Q9GYV5 (NEMO_DROME) |url=https://www.uniprot.org/uniprot/Q9GYV5 |website=Uniprot.org |quote=Interpro family: IPR034735 NEMO_ZF}}

• Imd: human orthologue = RIP1
• Tak1: human orthologue = Tak1
• TAB2: human orthologue = TAB2
• Dredd: human orthologue = caspase-8
• FADD: human orthologue = FADD
• Key/Ikkγ: human orthologue = NEMO
• Ird5: human orthologue = IKK2
• Relish: human orthologues = p65/p50 and IκB
• Iap2: human orthologue = cIAP2
• UEV1a: human orthologue = UEV1a
• bend: human orthologue = UBC13

While the exact epistasis of Imd pathway signalling components is continually scrutinized, the mechanistic order of many key components of the pathway is well-established. The following sections discuss Imd signalling as it is found in Drosophila melanogaster, where it is exceptionally well-characterized. Imd signalling is activated by a series of steps from recognition of a bacterial substance (e.g. peptidoglycan) to the transmission of that signal leading to activation of the NF-κB transcription factor Relish. Activated Relish then forms dimers that move into the nucleus and bind to DNA leading to the transcription of antimicrobial peptides and other effectors.

The sensing of bacterial signals is performed by peptidoglycan recognition protein LC (PGRP-LC), a transmembrane protein with an intracellular domain. Binding of bacterial peptidoglycan leads to dimerization of PGRP-LC which generates the conformation needed to bind and activate the Imd protein. However alternate isoforms of PGRP-LC can also be expressed with different functions: PGRP-LCx recognizes polymeric peptidoglycan, while PGRP-LCa does not bind peptidoglycan directly but acts alongside PGRP-LCx to bind monomeric peptidoglycan fragments (called tracheal cytotoxin or "TCT"). Another PGRP (PGRP-LE) also acts intracellularly to bind TCT that has crossed the cell membrane or is derived from an intracellular infection. PGRP-LA promotes the activation of Imd signalling in epithelial cells, but the mechanism is still unknown.

Other PGRPs can inhibit the activation of Imd signalling by binding bacterial signals or inhibiting host signalling proteins: PGRP-LF is a transmembrane PGRP that lacks an intracellular domain and does not bind peptidoglycan. Instead PGRP-LF forms dimers with PGRP-LC preventing PGRP-LC dimerization and consequently activation of Imd signalling. A number of secreted PGRPs have amidase activity that downregulate the Imd pathway by digesting peptidoglycan into short, non-immunogenic fragments. These include PGRP-LB, PGRP-SC1A, PGRP-SC1B, and PGRP-SC2. Additionally, PGRP-LB is the major regulator in the gut.{{cite journal | vauthors = Zaidman-Rémy A, Hervé M, Poidevin M, Pili-Floury S, Kim MS, Blanot D, Oh BH, Ueda R, Mengin-Lecreulx D, Lemaitre B | title = The Drosophila amidase PGRP-LB modulates the immune response to bacterial infection | journal = Immunity | volume = 24 | issue = 4 | pages = 463–473 | date = April 2006 | pmid = 16618604 | doi = 10.1016/j.immuni.2006.02.012 | doi-access = free }}

File:AMP Ecc15-19-02-2019.tif infected by GFP-producing bacteria. Red-eyed flies lacking antimicrobial peptide genes are susceptible to infection, while white-eyed flies have a wild-type immune response.]]

The principle intracellular signalling protein is Imd, a death domain-containing protein that binds with FADD and Dredd to form a complex. Dredd is activated following ubiquitination by the Iap2 complex (involving Iap2, UEV1a, bend, and eff), which allows Dredd to cleave the 30 residue N-terminus of Imd, allowing it to also be ubiquitinated by Iap2. Following this, the Tak1/TAB2 complex binds to the activated form of Imd and subsequently activates the IKKγ/Ird5 complex through phosphorylation. This IKKγ complex activates Relish by phosphorylation, leading to cleavage of Relish and thereby producing both N-terminal and C-terminal Relish fragments. The N-terminal Relish fragments dimerize leading to their translocation into the nucleus where these dimers bind to Relish-family NF-κB binding sites. Binding of Relish promotes the transcription of effectors such as antimicrobial peptides.

While Relish is integral for transcription of Imd pathway effectors, there is additional cooperation with other pathways such as Toll and JNK. The TAK1/TAB2 complex is key to propagating intracellular signalling of not only the Imd pathway, but also the JNK pathway. As a result, mutants for JNK signalling have severely reduced expression of Imd pathway antimicrobial peptides.{{cite journal | vauthors = Delaney JR, Stöven S, Uvell H, Anderson KV, Engström Y, Mlodzik M | title = Cooperative control of Drosophila immune responses by the JNK and NF-kappaB signaling pathways | journal = The EMBO Journal | volume = 25 | issue = 13 | pages = 3068–3077 | date = July 2006 | pmid = 16763552 | pmc = 1500970 | doi = 10.1038/sj.emboj.7601182 }}

Imd signalling regulates a number of effector peptides and proteins that are produced en masse following immune challenge.{{cite journal | vauthors = De Gregorio E, Spellman PT, Tzou P, Rubin GM, Lemaitre B | title = The Toll and Imd pathways are the major regulators of the immune response in Drosophila | journal = The EMBO Journal | volume = 21 | issue = 11 | pages = 2568–2579 | date = June 2002 | pmid = 12032070 | pmc = 126042 | doi = 10.1093/emboj/21.11.2568 }} This includes many of the major antimicrobial peptide genes of Drosophila, particularly: Diptericin, Attacin, Drosocin, Cecropin, and Defensin.{{cite book | vauthors = Imler JL, Bulet P | title = Antimicrobial peptides in Drosophila: structures, activities and gene regulation | volume = 86 | pages = 1–21 | date = 2005 | pmid = 15976485 | doi = 10.1159/000086648 | isbn = 3-8055-7862-8 | series = Chemical Immunology and Allergy }} The Imd pathway regulates hundreds of genes after infection, however the antimicrobial peptides play one of the most essential roles of Imd signalling in defence. Flies lacking multiple antimicrobial peptide genes succumb to infections by a broad suite of Gram-negative bacteria.{{cite journal | vauthors = Hanson MA, Dostálová A, Ceroni C, Poidevin M, Kondo S, Lemaitre B | title = Synergy and remarkable specificity of antimicrobial peptides in vivo using a systematic knockout approach | journal = eLife | volume = 8 | pages = e44341 | date = February 2019 | pmid = 30803481 | pmc = 6398976 | doi = 10.7554/eLife.44341 | doi-access = free }}{{cite journal | vauthors = Carboni AL, Hanson MA, Lindsay SA, Wasserman SA, Lemaitre B | title = Cecropins contribute to Drosophila host defense against a subset of fungal and Gram-negative bacterial infection | journal = Genetics | volume = 220 | issue = 1 | pages = iyab188 | date = January 2022 | pmid = 34791204 | pmc = 8733632 | doi = 10.1093/genetics/iyab188 }} Classical thinking suggested that antimicrobial peptides worked as a generalist cocktail in defence, where each peptide provided a small and somewhat redundant contribution.{{cite journal | vauthors = Lazzaro BP | title = Natural selection on the Drosophila antimicrobial immune system | journal = Current Opinion in Microbiology | volume = 11 | issue = 3 | pages = 284–289 | date = June 2008 | pmid = 18555739 | pmc = 2527063 | doi = 10.1016/j.mib.2008.05.001 }} However Hanson and colleagues found that single antimicrobial peptide genes displayed an unexpectedly high degree of specificity for defence against specific microbes. The fly Diptericin A gene is essential for defence against the bacterium Providencia rettgeri (also suggested by an earlier evolutionary study{{cite journal | vauthors = Unckless RL, Howick VM, Lazzaro BP | title = Convergent Balancing Selection on an Antimicrobial Peptide in Drosophila | journal = Current Biology | volume = 26 | issue = 2 | pages = 257–262 | date = January 2016 | pmid = 26776733 | pmc = 4729654 | doi = 10.1016/j.cub.2015.11.063 | bibcode = 2016CBio...26..257U }}). A second specificity is encoded by Diptericin B, which defends flies against Acetobacter bacteria of the fly microbiome.{{Cite journal |last1=Hanson |first1=M. A. |last2=Grollmus |first2=L. |last3=Lemaitre |first3=B. |date=2023-07-21 |title=Ecology-relevant bacteria drive the evolution of host antimicrobial peptides in Drosophila |url=https://www.science.org/doi/10.1126/science.adg5725 |journal=Science |language=en |volume=381 |issue=6655 |pages=eadg5725 |doi=10.1126/science.adg5725 |pmid=37471548 |issn=0036-8075|hdl=10871/133708 |s2cid=259115731 |hdl-access=free }} A third specificity is encoded by the gene Drosocin. Flies lacking Drosocin are highly susceptible to Enterobacter cloacae infection.{{cite journal | vauthors = Hanson MA, Kondo S, Lemaitre B | title = Drosophila immunity: the Drosocin gene encodes two host defence peptides with pathogen-specific roles | journal = Proceedings. Biological Sciences | volume = 289 | issue = 1977 | pages = 20220773 | date = June 2022 | pmid = 35730150 | pmc = 9233930 | doi = 10.1098/rspb.2022.0773 }} The Drosocin gene itself encodes two peptides (named Drosocin and Buletin), wherein it is specifically the Drosocin peptide that is responsible for defence against E. cloacae, while the Buletin peptide instead mediates a specific defence against another bacterium, Providencia burhodogranariea. These works accompany others on antimicrobial peptides and effectors regulated by the Drosophila Toll pathway, which also display a specific importance in defence against certain fungi or bacteria.{{cite journal | vauthors = Clemmons AW, Lindsay SA, Wasserman SA | title = An effector Peptide family required for Drosophila toll-mediated immunity | journal = PLOS Pathogens | volume = 11 | issue = 4 | pages = e1004876 | date = April 2015 | pmid = 25915418 | pmc = 4411088 | doi = 10.1371/journal.ppat.1004876 | veditors = Silverman N | doi-access = free }}{{cite journal | vauthors = Cohen LB, Lindsay SA, Xu Y, Lin SJ, Wasserman SA | title = The Daisho Peptides Mediate Drosophila Defense Against a Subset of Filamentous Fungi | journal = Frontiers in Immunology | volume = 11 | pages = 9 | date = 2020 | pmid = 32038657 | pmc = 6989431 | doi = 10.3389/fimmu.2020.00009 | doi-access = free }}{{cite journal | vauthors = Hanson MA, Cohen LB, Marra A, Iatsenko I, Wasserman SA, Lemaitre B | title = The Drosophila Baramicin polypeptide gene protects against fungal infection | journal = PLOS Pathogens | volume = 17 | issue = 8 | pages = e1009846 | date = August 2021 | pmid = 34432851 | pmc = 8423362 | doi = 10.1371/journal.ppat.1009846 | veditors = Lin X | doi-access = free }}

This work on Drosophila immune antimicrobial peptides and effectors has greatly revised the former view that such peptides are generalist molecules. The modern interpretation is now that specific molecules might provide a somewhat redundant layer of defence, but also single peptides can have critical importance, individually, against relevant microbes.{{cite journal | vauthors = Lin SJ, Cohen LB, Wasserman SA | title = Effector specificity and function in Drosophila innate immunity: Getting AMPed and dropping Boms | journal = PLOS Pathogens | volume = 16 | issue = 5 | pages = e1008480 | date = May 2020 | pmid = 32463841 | pmc = 7255597 | doi = 10.1371/journal.ppat.1008480 | veditors = Silverman N | doi-access = free }}{{cite journal | vauthors = Hanson MA, Lemaitre B | title = New insights on Drosophila antimicrobial peptide function in host defense and beyond | journal = Current Opinion in Immunology | volume = 62 | pages = 22–30 | date = February 2020 | pmid = 31835066 | doi = 10.1016/j.coi.2019.11.008 | s2cid = 209357523 | hdl = 10871/133705 | hdl-access = free }}{{cite journal | vauthors = Lazzaro BP, Zasloff M, Rolff J | title = Antimicrobial peptides: Application informed by evolution | journal = Science | volume = 368 | issue = 6490 | pages = eaau5480 | date = May 2020 | pmid = 32355003 | pmc = 8097767 | doi = 10.1126/science.aau5480 }}{{cite journal | vauthors = Bosch TC, Zasloff M | title = Antimicrobial Peptides-or How Our Ancestors Learned to Control the Microbiome | journal = mBio | volume = 12 | issue = 5 | pages = e0184721 | date = October 2021 | pmid = 34579574 | pmc = 8546549 | doi = 10.1128/mBio.01847-21 }}

File:Acyrthosiphon pisum (pea aphid)-PLoS.jpg

The Imd pathway appears to have evolved in the last common ancestor of centipedes and insects. However certain lineages of insects have since lost core components of Imd signalling. The first-discovered and most famous example is the pea aphid Acyrthosiphon pisum. It is thought that plant-feeding aphids have lost Imd signalling as they bear a number of bacterial endosymbionts, including both nutritional symbionts that would be disrupted by aberrant expression of antimicrobial peptides, and defensive symbionts that cover for some of the immune deficiency caused by loss of Imd signalling.{{cite journal | vauthors = Gerardo NM, Altincicek B, Anselme C, Atamian H, Barribeau SM, de Vos M, Duncan EJ, Evans JD, Gabaldón T, Ghanim M, Heddi A, Kaloshian I, Latorre A, Moya A, Nakabachi A, Parker BJ, Pérez-Brocal V, Pignatelli M, Rahbé Y, Ramsey JS, Spragg CJ, Tamames J, Tamarit D, Tamborindeguy C, Vincent-Monegat C, Vilcinskas A | title = Immunity and other defenses in pea aphids, Acyrthosiphon pisum | journal = Genome Biology | volume = 11 | issue = 2 | pages = R21 | date = 2010 | pmid = 20178569 | pmc = 2872881 | doi = 10.1186/gb-2010-11-2-r21 | author-link = Nicole Gerardo | doi-access = free }} It has also been suggested that antimicrobial peptides, the downstream components of Imd signalling, may be detrimental to fitness and lost by insects with exclusively plant-feeding ecologies.{{cite journal | vauthors = Hanson MA, Lemaitre B, Unckless RL | title = Dynamic Evolution of Antimicrobial Peptides Underscores Trade-Offs Between Immunity and Ecological Fitness | journal = Frontiers in Immunology | volume = 10 | pages = 2620 | date = 2019 | pmid = 31781114 | pmc = 6857651 | doi = 10.3389/fimmu.2019.02620 | doi-access = free }}

While the Toll and Imd signalling pathways of Drosophila are commonly depicted as independent for explanatory purposes, the underlying complexity of Imd signalling involves a number of likely mechanisms wherein Imd signalling interacts with other signalling pathways including Toll and JNK. While the paradigm of Toll and Imd as largely independent provides a useful context for the study of immune signalling, the universality of this paradigm as it applies to other insects has been questioned. In Plautia stali stinkbugs, suppression of either Toll or Imd genes simultaneously leads to reduced activity of classic Toll and Imd effectors from both pathways.{{cite journal | vauthors = Nishide Y, Kageyama D, Yokoi K, Jouraku A, Tanaka H, Futahashi R, Fukatsu T | title = Functional crosstalk across IMD and Toll pathways: insight into the evolution of incomplete immune cascades | journal = Proceedings. Biological Sciences | volume = 286 | issue = 1897 | pages = 20182207 | date = February 2019 | pmid = 30963836 | pmc = 6408883 | doi = 10.1098/rspb.2018.2207 }}

• The pea aphid Acyrthosiphon pisum
• The bed bug Cimex lectularius{{cite journal | vauthors = Benoit JB, Adelman ZN, Reinhardt K, Dolan A, Poelchau M, Jennings EC, Szuter EM, Hagan RW, Gujar H, Shukla JN, Zhu F, Mohan M, Nelson DR, Rosendale AJ, Derst C, Resnik V, Wernig S, Menegazzi P, Wegener C, Peschel N, Hendershot JM, Blenau W, Predel R, Johnston PR, Ioannidis P, Waterhouse RM, Nauen R, Schorn C, Ott MC, Maiwald F, Johnston JS, Gondhalekar AD, Scharf ME, Peterson BF, Raje KR, Hottel BA, Armisén D, Crumière AJ, Refki PN, Santos ME, Sghaier E, Viala S, Khila A, Ahn SJ, Childers C, Lee CY, Lin H, Hughes DS, Duncan EJ, Murali SC, Qu J, Dugan S, Lee SL, Chao H, Dinh H, Han Y, Doddapaneni H, Worley KC, Muzny DM, Wheeler D, Panfilio KA, Vargas Jentzsch IM, Vargo EL, Booth W, Friedrich M, Weirauch MT, Anderson MA, Jones JW, Mittapalli O, Zhao C, Zhou JJ, Evans JD, Attardo GM, Robertson HM, Zdobnov EM, Ribeiro JM, Gibbs RA, Werren JH, Palli SR, Schal C, Richards S | title = Unique features of a global human ectoparasite identified through sequencing of the bed bug genome | journal = Nature Communications | volume = 7 | pages = 10165 | date = February 2016 | pmid = 26836814 | pmc = 4740739 | doi = 10.1038/ncomms10165 | bibcode = 2016NatCo...710165B }}
• The mite Tetranychus urticae{{cite journal | vauthors = Santos-Matos G, Wybouw N, Martins NE, Zélé F, Riga M, Leitão AB, Vontas J, Grbić M, Van Leeuwen T, Magalhães S, Sucena É | title = Tetranychus urticae mites do not mount an induced immune response against bacteria | journal = Proceedings. Biological Sciences | volume = 284 | issue = 1856 | pages = 20170401 | date = June 2017 | pmid = 28592670 | pmc = 5474072 | doi = 10.1098/rspb.2017.0401 }}

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