Drosophila caspases as guardians of host-microbe interactions

Kietz, Christa; Meinander, Annika

doi:10.1038/s41418-022-01038-4

Cited by 6 publications

(5 citation statements)

References 152 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5 A). Prominently featured in these pathways are receptor-proximal adaptor proteins (e.g., mammalian RIP1 or fly imd) that are activated by K63-linked ubiquitylation (K63-Ub) [ 59 , 112 , 113 ]. The protein complex that carries out these crucial post-translational modifications includes the E2 conjugating enzymes and cofactors Ubc13/bendless (Ben), Uev1a, and Ubc5/effete, along with two other RING-domain E3 ligases, Diap2 or Traf6 (see Fig.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of innate immune signaling in animal models of spinal muscular atrophy

Garcia,

Steiner,

Raimer

et al. 2024

BMC Biol

View full text Add to dashboard Cite

Background Spinal muscular atrophy (SMA) is a devastating neuromuscular disease caused by hypomorphic loss of function in the survival motor neuron (SMN) protein. SMA presents across a broad spectrum of disease severity. Unfortunately, genetic models of intermediate SMA have been difficult to generate in vertebrates and are thus unable to address key aspects of disease etiology. To address these issues, we developed a Drosophila model system that recapitulates the full range of SMA severity, allowing studies of pre-onset biology as well as late-stage disease processes. Results Here, we carried out transcriptomic and proteomic profiling of mild and intermediate Drosophila models of SMA to elucidate molecules and pathways that contribute to the disease. Using this approach, we elaborated a role for the SMN complex in the regulation of innate immune signaling. We find that mutation or tissue-specific depletion of SMN induces hyperactivation of the immune deficiency (IMD) and Toll pathways, leading to overexpression of antimicrobial peptides (AMPs) and ectopic formation of melanotic masses in the absence of an external challenge. Furthermore, the knockdown of downstream targets of these signaling pathways reduced melanotic mass formation caused by SMN loss. Importantly, we identify SMN as a negative regulator of a ubiquitylation complex that includes Traf6, Bendless, and Diap2 and plays a pivotal role in several signaling networks. Conclusions In alignment with recent research on other neurodegenerative diseases, these findings suggest that hyperactivation of innate immunity contributes to SMA pathology. This work not only provides compelling evidence that hyperactive innate immune signaling is a primary effect of SMN depletion, but it also suggests that the SMN complex plays a regulatory role in this process in vivo. In summary, immune dysfunction in SMA is a consequence of reduced SMN levels and is driven by cellular and molecular mechanisms that are conserved between insects and mammals.

show abstract

Section: Discussionmentioning

confidence: 99%

Dysregulation of innate immune signaling in animal models of spinal muscular atrophy

Garcia,

Steiner,

Raimer

et al. 2024

BMC Biol

View full text Add to dashboard Cite

show abstract

“…Prominently featured in these pathways are receptor-proximal adaptor proteins (e.g. RIP1/Imd) that are activated by K63-linked ubiquitylation (K63-Ub) (Valanne et al 2011;Lindsay and Wasserman 2013;Kietz and Meinander 2023). The protein complex that carries out these crucial post-translational modifications includes the E2 conjugating enzymes and cofactors Ubc13/bendless (Ben), Uev1a, and Ubc5/effete, along with two other RING-domain E3 ligases, Diap2 or Traf6 (see Fig.…”

Section: Smn K63-linked Polyubiquitylation and Immune Signaling Networkmentioning

confidence: 99%

Dysregulation of innate immune signaling in animal models of Spinal Muscular Atrophy

Garcia,

Steiner,

Raimer

et al. 2023

Preprint

View full text Add to dashboard Cite

BackgroundSpinal Muscular Atrophy (SMA) is a devastating neuromuscular disease caused by hypomorphic loss of function in the Survival Motor Neuron (SMN) protein. SMA presents across broad spectrum of disease severity. Unfortunately, vertebrate models of intermediate SMA have been difficult to generate and are thus unable to address key aspects of disease etiology. To address these issues, we developed aDrosophilamodel system that recapitulates the full range of SMA severity, allowing studies of pre-onset biology as well as late-stage disease processes.ResultsHere, we carried out transcriptomic and proteomic profiling of mild and intermediateDrosophilamodels of SMA to elucidate molecules and pathways that contribute to the disease. Using this approach, we elaborated a role for the SMN complex in the regulation of innate immune signaling. We find that mutation or tissue-specific depletion of SMN induces hyperactivation of the Immune Deficiency (IMD) and Toll pathways, leading to overexpression of antimicrobial peptides (AMPs) and ectopic formation of melanotic masses in the absence of an external challenge. Furthermore, knockdown of downstream targets of these signaling pathways reduced melanotic mass formation caused by SMN loss. Importantly, we identify SMN as a negative regulator of an ubiquitylation complex that includes Traf6, Bendless and Diap2, and plays a pivotal role in several signaling networks.ConclusionsIn alignment with recent research on other neurodegenerative diseases, these findings suggest that hyperactivation of innate immunity contributes to SMA pathology. This work not only provides compelling evidence that hyperactive innate immune signaling is a primary effect of SMN depletion, but it also suggests that the SMN complex plays a regulatory role in this processin vivo. In summary, immune dysfunction in SMA is a consequence of reduced SMN levels and is driven by cellular and molecular mechanisms that are conserved between insects and mammals.

show abstract

“…Once in the nucleus, Stat92E binds to the promoter regions of its target genes. The JAK/STAT signaling pathway also upregulates Socs36E gene expression This illustration has been adopted from C. Kietz and A. Meinander et al ( 144 ).…”

Section: Melanogaster’s and T Molitor ’S ...mentioning

confidence: 99%

“…Pelle phosphorylates Cactus, an inhibitory protein. Meanwhile, the transcription factors Dorsal and Dorsal-related immunity factor (Dif) within the cytoplasm traverse into the nucleus, where they generate an array of antimicrobial peptides ( Figure 7 ) ( 161 ). Remarkably, the Toll signaling pathway’s activation is not initiated through direct contact with the microorganisms but rather upon detecting the cytokine-like polypeptide Spätzle, evidencing Semmelweis and Osiris genes’ influence in gram-positive-dependent Toll activation ( 94 ).…”

Section: T Molitor’s Gut Immune Responsementioning

confidence: 99%

Recent trends in insect gut immunity

Khan,

Kojour,

Han

2023

Front. Immunol.

View full text Add to dashboard Cite

The gut is a crucial organ in insect defense against various pathogens and harmful substances in their environment and diet. Distinct insect gut compartments possess unique functionalities contributing to their physiological processes, including immunity. The insect gut’s cellular composition is vital for cellular and humoral immunity. The peritrophic membrane, mucus layer, lumen, microvilli, and various gut cells provide essential support for activating and regulating immune defense mechanisms. These components also secrete molecules and enzymes that are imperative in physiological activities. Additionally, the gut microbiota initiates various signaling pathways and produces vitamins and minerals that help maintain gut homeostasis. Distinct immune signaling pathways are activated within the gut when insects ingest pathogens or hazardous materials. The pathway induced depends on the infection or pathogen type; include immune deficiency (imd), Toll, JAK/STAT, Duox-ROS, and JNK/FOXO regulatory pathways. These pathways produce different antimicrobial peptides (AMPs) and maintain gut homeostasis. Furthermore, various signaling mechanisms within gut cells regulate insect gut recovery following infection. Although some questions regarding insect gut immunity in different species require additional study, this review provides insights into the insect gut’s structure and composition, commensal microorganism roles in Drosophila melanogaster and Tenebrio molitor life cycles, different signaling pathways involved in gut immune systems, and the insect gut post-infection recovery through various signaling mechanisms.

show abstract

Drosophila caspases as guardians of host-microbe interactions

Cited by 6 publications

References 152 publications

Dysregulation of innate immune signaling in animal models of spinal muscular atrophy

Dysregulation of innate immune signaling in animal models of spinal muscular atrophy

Dysregulation of innate immune signaling in animal models of Spinal Muscular Atrophy

Recent trends in insect gut immunity

Contact Info

Product

Resources

About