Smolstatin1, a unique cystatin-like stefin of Sphaerospora molnari, is essential for parasite development

Highlights

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    Smolstatin1 clusters with other myxozoan cystatin-like stefins
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    Smolstatin1 is upregulated during sporogony and localizes to cell compartments and parasite surface
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    Smolstatin1 inhibits host and parasite cysteine proteases, mainly cathepsin L
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    RNAi-mediated Smolstatin1 knockdown impairs parasite motility and alters cell morphology
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    Smolstatin1 crystallizes as an unusual domain-swapped dimer

Abstract

Stefins, members of the cystatin superfamily, regulate cysteine proteases, yet their roles in early-branching metazoans remain poorly defined. Here, we characterize Smolstatin1, a cystatin-like stefin from the myxozoan Sphaerospora molnari, a common carp pathogen. Phylogenetic analysis places Smolstatin1 within a monophyletic clade of myxozoan cystatin-like stefins that groups with homologues from foodborne flukes and canonical metazoan stefins. Smolstatin1 is expressed throughout intrapiscine development, is upregulated during sporogony, and localizes to membrane-bound compartments and the blood-stage surface. Recombinant Smolstatin1 inhibits parasite and host cysteine proteases, with strongest activity toward cathepsin L-like enzymes and weaker activity against legumain, while showing negligible effects on serine proteases. RNAi-mediated knockdown reduces parasite motility and alters cell integrity, suggesting a role in parasite fitness and development. Structural analysis reveals an unusual domain-swapped dimer. Although antigenic, Smolstatin1 vaccination does not protect fish from infection. Together, these findings identify Smolstatin1 as a key protease regulator and expand our understanding of cystatin evolution and function.

Read full article for free (open access):
https://www.sciencedirect.com/science/article/pii/S2666517426000660



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