The emerging roles of ZDHHCs-mediated protein palmitoylation in the antiviral innate immune responses.

Post-translational modifications (PTMs) play a pivotal role in expanding functional protein diversity. During viral infection, pathogen-associated molecular patterns derived from viruses are recognized by pattern recognition receptors present in the membrane surface and the cytoplasm of infected cells, which subsequently induces the antiviral innate immunity to protect the host from the invading viruses. Fatty acylation modification is identified as a post-translation lipid modification process. Mounting evidence is presented that lipid modification functions as a novel regulatory mechanism of antiviral innate immunity. In mammalian cells, DHHC (Asp-His-His-Cys) domain is indispensable for most of the palmitoylation modification, which belongs to fatty acylation. ZDHHC family proteins are composed of 23 members in human cells. In this review, we will summarize the recent findings of the regulatory mechanism of the palmitoylation in the process of host antiviral innate immunity against viruses.

Non-C-mannosylable mucin CYS domains hindered proper folding and secretion of mucin.

The CYS domain occurs in multiple copies in many gel-forming mucins. It is believed that CYS domains can interact with each other in a reversible manner, suggesting a key role of the domain in gel formation. This domain always contains in its amino-terminal sequence the C-mannosylation motif WXXW, but whether the CYS domain is C-mannosylated is debated, and the putative role of C-mannosylation of the domain is unclear. We prepared recombinant CYS domains of the human mucin MUC5B with (WXXW→AXXW) and without a single amino acid mutation and mini-5B mucins made of a large Ser/Thr/Pro region flanked by two CYS domains with the WXXW motif or with the mutated AXXW motif on the first, second or both CYS domains. We found that the single CYS domain and the two CYS domains of mini-5B mucin must be C-mannosylable for the efficient maturation and secretion of the recombinant molecules; otherwise, they are retained in the cell and co-localized with a resident enzyme of the endoplasmic reticulum.

Identification of candidate transmission-blocking antigen genes in Theileria annulata and related vector-borne apicomplexan parasites.

BACKGROUND: Vector-borne apicomplexan parasites are a major cause of mortality and morbidity to humans and livestock globally. The most important disease syndromes caused by these parasites are malaria, babesiosis and theileriosis. Strategies for control often target parasite stages in the mammalian host that cause disease, but this can result in reservoir infections that promote pathogen transmission and generate economic loss. Optimal control strategies should protect against clinical disease, block transmission and be applicable across related genera of parasites. We have used bioinformatics and transcriptomics to screen for transmission-blocking candidate antigens in the tick-borne apicomplexan parasite, Theileria annulata. RESULTS: A number of candidate antigen genes were identified which encoded amino acid domains that are conserved across vector-borne Apicomplexa (Babesia, Plasmodium and Theileria), including the Pfs48/45 6-cys domain and a novel cysteine-rich domain. Expression profiling confirmed that selected candidate genes are expressed by life cycle stages within infected ticks. Additionally, putative B cell epitopes were identified in the T. annulata gene sequences encoding the 6-cys and cysteine rich domains, in a gene encoding a putative papain-family cysteine peptidase, with similarity to the Plasmodium SERA family, and the gene encoding the T. annulata major merozoite/piroplasm surface antigen, Tams1. CONCLUSIONS: Candidate genes were identified that encode proteins with similarity to known transmission blocking candidates in related parasites, while one is a novel candidate conserved across vector-borne apicomplexans and has a potential role in the sexual phase of the life cycle. The results indicate that a 'One Health' approach could be utilised to develop a transmission-blocking strategy effective against vector-borne apicomplexan parasites of animals and humans.

Biological modeling of mucus to modulate mucus barriers.

A recent study using a transgenic mouse, whose intestinal mucus contains a molecule made of 12 copies of a domain found in many gelling mucins, demonstrates that it is possible to strengthen mucus properties in situ, leading to promising new treatment strategies in diseases in which the mucosal barrier is impaired.

Gel-forming mucin interactome drives mucus viscoelasticity.

Mucus is a hydrogel that constitutes the first innate defense in all mammals. The main organic component of mucus, gel-forming mucins, forms a complex network through both reversible and irreversible interactions that drive mucus gel formation. Significant advances in the understanding of irreversible gel-forming mucins assembly have been made using recombinant protein approaches. However, little is known about the reversible interactions that may finely modulate mucus viscoelasticity, which can be characterized using rheology. This approach can be used to investigate both the nature of gel-forming mucins interactions and factors that influence hydrogel formation. This knowledge is directly relevant to the development of new drugs to modulate mucus viscoelasticity and to restore normal mucus functions in diseases such as in cystic fibrosis. The aim of the present review is to summarize the current knowledge about the relationship between the mucus protein matrix and its functions, with emphasis on mucus viscoelasticity.