An ML protein from the silkworm Bombyx mori may function as a key accessory protein for lipopolysaccharide signaling

Zhang, Ruonan; Ren, Feifei; Zhou, Chun; Xu, Junfeng; Huiuk, Yi; Ye, Mingqiang; Deng, Xiao‐Juan; Cao, Yang; Yu, Xiao‐Qiang; Yang, Wan-Ying

doi:10.1016/j.dci.2018.07.012

Cited by 12 publications

(21 citation statements)

References 42 publications

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“…Results reported in this study provide evidence that BmMD-2A and BmMD-2B both complex with BmToll9. Our previous results further indicate that BmMD-2A more strongly binds to LPS than PGN or lipoteichoic acid while showing no binding to laminarin or mannan (27). Results from this study also support that BmMD-2B binds LPS while previous results indicate it may additionally bind certain glucans (43,44).…”

Section: Discussionsupporting

confidence: 81%

“…S3C). As previously noted, mammalian TLR4s require the ML protein MD-2 for LPS recognition and downstream signaling (32)(33)(34), while B. mori encodes three ML proteins that, as previously noted, were named BmEsr16, BmPP, and BmML-1 (27) but in this study were called BmMD-2A, BmMD-2B, and BmML-1, respectively. Antibodies detected BmMD-2A, BmMD-2B, and BmML-1 in fat body, hemocyte, midgut, and cell-free hemolymph (plasma) samples, which strongly suggested each was secreted (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 59%

“…As earlier noted, PGN likewise activates AMP gene expression in Lepidoptera (moths and butterflies) including B. mori and M. sexta (25,26). However, prior studies indicated that LPS in association with BmMD-2A (BmEsr16) also stimulates the expression of select AMP genes (25)(26)(27). We thus hypothesized that BmMD-2A and possibly other ML proteins function as accessory factors that complex with one or more BmToll receptors in a manner similar to LPS inducing downstream signaling by TLR4-MD-2 in mammals (20,38).…”

Section: Discussionmentioning

confidence: 93%

“…In contrast, both ultrapure PGN and LPS activate AMP gene expression in Lepidoptera (moths and butterflies) like Bombyx mori and Manduca sexta (25,26). The factors involved in LPS signaling are largely unknown although B. mori, M. sexta, and other insects encode MD-2-related lipidrecognition (ML) protein family members (27)(28)(29).…”

mentioning

confidence: 99%

“…We recently identified three ML proteins in B. mori that were originally named BmEsr16, BmPP, and BmML-1, and presented evidence which implicated BmEsr16 in LPS-induced expression of certain AMP genes (27). Given sequence similarities between insect Toll9 members and mammalian TLR4, this study addressed…”

mentioning

confidence: 99%

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Toll9 fromBombyx morifunctions as a pattern recognition receptor that shares features with Toll-like receptor 4 from mammals

Zhang

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Toll/Toll-like receptors (TLRs) are key regulators of the innate immune system in both invertebrates and vertebrates. However, while mammalian TLRs directly recognize pathogen-associated molecular patterns, the insect Toll pathway is thought to be primarily activated by binding Spätzle cytokines that are processed from inactive precursors in response to microbial infection. Phylogenetic and structural data generated in this study supported earlier results showing that Toll9 members differ from other insect Tolls by clustering with the mammalian TLR4 group, which recognizes lipopolysaccharide (LPS) through interaction with myeloid differentiation-2 (MD-2)–like proteins. Functional experiments showed that BmToll9 from the silkmoth Bombyx mori also recognized LPS through interaction with two MD-2–like proteins, previously named BmEsr16 and BmPP, that we refer to in this study as BmMD-2A and BmMD-2B, respectively. A chimeric BmToll9–TLR4 receptor consisting of the BmToll9 ectodomain and mouse TLR4 transmembrane and Toll/interleukin-1 (TIR) domains also activated LPS-induced release of inflammatory factors in murine cells but only in the presence of BmMD-2A or BmMD-2B. Overall, our results indicate that BmToll9 is a pattern recognition receptor for LPS that shares conserved features with the mammalian TLR4–MD-2–LPS pathway.

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Section: Discussionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Toll9 fromBombyx morifunctions as a pattern recognition receptor that shares features with Toll-like receptor 4 from mammals

Zhang

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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BmPGPR‐L4 is a negative regulator of the humoral immune response in the silkworm Bombyx mori

Yang,

Lin,

et al. 2024

Arch Insect Biochem Physiol

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Toll, immune deficiency and prophenoloxidase cascade represent vital immune signaling pathways in insects. Peptidoglycan recognition proteins (PGRPs) are innate immune receptors that activate and regulate the immune signaling pathways. Previously, we reported that BmPGPR‐L4 was induced in the silkworm Bombyx mori larvae by bacteria and peptidoglycan challenges. Here, we focused on the function of BmPGRP‐L4 in regulating the expression of antimicrobial peptides (AMPs). The hemolymph from BmPGRP‐L4‐silenced larvae exhibited an enhanced inhibitory effect on the growth of Escherichia coli, either by growth curve or inhibitory zone experiments. Coincidentally, most of the AMP genes were upregulated after RNAi of BmPGRP‐L4. Oral administration of heat‐inactivated E. coli and Staphylococcus aureus after RNAi of BmPGRP‐L4 resulted in the increased expression of BmPGRP‐L4 in different tissues of the silkworm larvae, revealing an auto‐regulatory mechanism. By contrast, the expression of most AMP genes was downregulated by oral bacterial administration after RNAi of BmPGRP‐L4. The above results demonstrate that BmPGRP‐L4 recognizes bacterial pathogen‐associated molecular patterns and negatively regulates AMP expression to achieve immunological homeostasis. As a negative regulator, BmPGPR‐L4 is proposed to be involved in the feedback regulation of the immune signaling pathways of the silkworm to prevent excessive activation of the immune response.

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A novel ML domain-containing protein (SpMD2) functions as a potential LPS receptor involved in anti-Vibrio immune response

Wang

Zhang

et al. 2020

Developmental & Comparative Immunology

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An ML protein from the silkworm Bombyx mori may function as a key accessory protein for lipopolysaccharide signaling

Cited by 12 publications

References 42 publications

Toll9 fromBombyx morifunctions as a pattern recognition receptor that shares features with Toll-like receptor 4 from mammals

Toll9 fromBombyx morifunctions as a pattern recognition receptor that shares features with Toll-like receptor 4 from mammals

BmPGPR‐L4 is a negative regulator of the humoral immune response in the silkworm Bombyx mori

A novel ML domain-containing protein (SpMD2) functions as a potential LPS receptor involved in anti-Vibrio immune response

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