Serpins in arthropod biology

Meekins, David A.; Kanost, Michael R.; Michel, Kristin

doi:10.1016/j.semcdb.2016.09.001

Cited by 144 publications

(146 citation statements)

References 161 publications

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“…Serpins are the largest and most broadly distributed superfamily of protease inhibitors, which are critical requirements in the maintenance of immune homeostasis . Serpins are evolutionarily conserved and also widely distributed in arthropods . Large numbers of protease inhibitors were found to be expressed in the tick salivary glands, including Cystatin, Serpin and Kunitz‐like family .…”

Section: Introductionmentioning

confidence: 99%

The immunosuppressive functions of two novel tick serpins, HlSerpin‐a and HlSerpin‐b, from Haemaphysalis longicornis

et al. 2019

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Summary Serpins are evolutionarily conserved serine protease inhibitors that are widely distributed in animals, plants and microbes. In this study, we reported the cloning and functional characterizations of two novel serpin genes, HlSerpin‐a and HlSerpin‐b, from the hard tick Haemaphysalis longicornis of China. Recombinant HlSerpin‐a and HlSerpin‐b displayed protease inhibitory activities against multiple mammalian proteases. Similar to other tick serpins, HlSerpin‐a and HlSerpin‐b suppressed the expression of inflammatory cytokines such as TNF‐α, interleukin (IL)‐6 and IL‐1β from lipopolysaccharide‐stimulated mouse bone‐marrow‐derived macrophages (BMDMs) or mouse bone‐marrow‐derived dendritic cells (BMDCs). The minimum active region (reaction centre loop) of HlSerpin‐a, named SA‐RCL, showed similar biological activities as HlSerpin‐a in the protease inhibition and immune suppression assays. The immunosuppressive activities of full‐length HlSerpin‐a and SA‐RCL are impaired in Cathepsin G or Cathepsin B knockout mouse macrophages, suggesting that the immunomodulation functions of SA and SA‐RCL are dependent on their protease inhibitory activity. Finally, we showed that both full‐length HlSerpins and SA‐RCL can relieve the joint swelling and inflammatory response in collagen‐induced mouse arthritis models. These results suggested that HlSerpin‐a and HlSerpin‐b are two functional arthropod serpins, and the minimal reactive peptide SA‐RCL is a potential candidate for drug development against inflammatory diseases.

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Section: Introductionmentioning

confidence: 99%

The immunosuppressive functions of two novel tick serpins, HlSerpin‐a and HlSerpin‐b, from Haemaphysalis longicornis

et al. 2019

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“…In such cascade pathways, a series of preexisting, inactive zymogens become active SPs through specific recognition and sequential proteolysis. The potency and duration of these responses are often controlled by SP inhibitors including serpins (Gubb et al, 2010; Meekins et al, 2017). Serpins are suicide inhibitors that form stable acyl-enzyme complexes with cognate proteases, only when the active SPs attack the serpins at their reactive center loop (Gettins, 2002).…”

Section: Introductionmentioning

confidence: 99%

Manduca sexta hemolymph protease-1, activated by an unconventional non-proteolytic mechanism, mediates immune responses

Wang

Yang

et al. 2017

Insect Biochemistry and Molecular Biology

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Tissue damage or pathogen invasion triggers the auto-proteolysis of an initiating serine protease (SP), rapidly leading to sequential cleavage activation of other cascade members to set off innate immune responses in insects. Recently, we presented evidence that Manduca sexta hemolymph protease-1 zymogen (proHP1) is a member of the SP system in this species, and may activate proHP6. HP6 stimulates melanization and induces antimicrobial peptide synthesis. Here we report that proHP1 adopts an active conformation (*) to carry out its function, without a requirement for proteolytic activation. Affinity chromatography using HP1 antibodies isolated from induced hemolymph the 48 kDa proHP1 and also a 90 kDa band (detected by SDS-PAGE under reducing conditions) containing proHP1 and several serpins, as revealed by mass spectrometric analysis. Identification of tryptic peptides from these 90 kDa complexes included peptides from the amino-terminal regulatory part of proHP1, indicating that proHP1* was not cleaved, and that it had formed a complex with the serpins. As suicide inhibitors, serpins form SDS-stable, acyl-complexes when they are attacked by active proteases, indicating that proHP1* was catalytically active. Detection of M. sexta serpin-1, 4, 9, 13 and smaller amounts of serpin-3, 5, 6 in the complexes suggests that it is regulated by multiple serpins in hemolymph. We produced site-directed mutants of proHP1b for cleavage by bovine blood coagulation factor Xa at the designed proteolytic activation site, to generate a form of proHP1b that could be activated by Factor Xa. However, proHP1b cut by Factor Xa failed to activate proHP6 and, via HP6, proHP8 or proPAP1. This negative result is consistent with the suggestion that proHP1* is a physiological mediator of immune responses. Further research is needed to investigate the conformational change that results in conversion of proHP1 to active proHP1*.

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“…Protease inhibitors, including serine, cysteine, aspartic, and metalloproteinase inhibitors are widely distributed in living organisms and have crucial roles in many biologic processes by regulating the protease activity (29)(30)(31). At least 23 different families of serine protease inhibitors have been reported; of which, 12 families are found in insects, including the Kazal, Kunitz, a-macroglobulin, and serpin families (29,30,32,33). The Kazal-type serine protease inhibitors (KSPIs) comprise a large family of protease inhibitors present in mammals, birds, crayfish, and insects.…”

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confidence: 99%

Juvenile hormone–dependent Kazal‐type serine protease inhibitor Greglin safeguards insect vitellogenesis and egg production

Guo

Yang

et al. 2018

The FASEB Journal

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In addition to preventing insect metamorphosis, juvenile hormone (JH) is known to stimulate aspects of insect reproduction. However, the molecular mechanisms of JH action in insect reproduction remain largely unknown. By reanalyzing the transcriptomic data from adults and other developmental stages of the migratory locust Locusta migratoria, we identified a gene coding for Kazal-type protease inhibitor, previously named Greglin. Greglin is specifically expressed in adult females and most abundant in the fat body and ovaries. Interestingly, Greglin is among the top 3 of highly expressed genes in adult female locusts, after 2 vitellogenin ( Vg) genes. Greglin is induced by JH and expressed at remarkably high levels in the vitellogenic stage. Knockdown of Greglin in adult female locusts results in accelerated degradation of serine protease substrate and significantly reduced levels of Greglin protein in hemolymph and ovaries. The consequent phenotypes include blocked oocyte maturation, arrested ovarian growth and shrunken follicular epithelium, as well as declines in egg number and hatchability. The data provide the first evidence, to our knowledge, that JH-dependent Greglin is involved in locust vitellogenesis and oocyte maturation likely by protecting vitellogenesis and other forms of yolk precursors from proteolysis. The result offers new insights into the regulation of JH and function of protease inhibitors in insect vitellogenesis, oocyte maturation and fecundity.-Guo, W., Wu, Z., Yang, L., Cai, Z., Zhao, L., Zhou, S. Juvenile hormone-dependent Kazal-type serine protease inhibitor Greglin safeguards insect vitellogenesis and egg production.

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Serpins in arthropod biology

Cited by 144 publications

References 161 publications

The immunosuppressive functions of two novel tick serpins, HlSerpin‐a and HlSerpin‐b, from Haemaphysalis longicornis

The immunosuppressive functions of two novel tick serpins, HlSerpin‐a and HlSerpin‐b, from Haemaphysalis longicornis

Manduca sexta hemolymph protease-1, activated by an unconventional non-proteolytic mechanism, mediates immune responses

Juvenile hormone–dependent Kazal‐type serine protease inhibitor Greglin safeguards insect vitellogenesis and egg production

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