Comparative analysis of FKBP family protein: evaluation, structure, and function in mammals and Drosophila melanogaster.

BACKGROUND: FK506-binding proteins (FKBPs) have become the subject of considerable interest in several fields, leading to the identification of several cellular and molecular pathways in which FKBPs impact prenatal development and pathogenesis of many human diseases. MAIN BODY: This analysis revealed differences between how mammalian and Drosophila FKBPs mechanisms function in relation to the immunosuppressant drugs, FK506 and rapamycin. Differences that could be used to design insect-specific pesticides. (1) Molecular phylogenetic analysis of FKBP family proteins revealed that the eight known Drosophila FKBPs share homology with the human FKBP12. This indicates a close evolutionary relationship, and possible origination from a common ancestor. (2) The known FKBPs contain FK domains, that is, a prolyl cis/trans isomerase (PPIase) domain that mediates immune suppression through inhibition of calcineurin. The dFKBP59, CG4735/Shutdown, CG1847, and CG5482 have a Tetratricopeptide receptor domain at the C-terminus, which regulates transcription and protein transportation. (3) FKBP51 and FKBP52 (dFKBP59), along with Cyclophilin 40 and protein phosphatase 5, function as Hsp90 immunophilin co-chaperones within steroid receptor-Hsp90 heterocomplexes. These immunophilins are potential drug targets in pathways associated with normal physiology and may be used to treat a variety of steroid-based diseases by targeting exocytic/endocytic cycling and vesicular trafficking. (4) By associating with presinilin, a critical component of the Notch signaling pathway, FKBP14 is a downstream effector of Notch activation at the membrane. Meanwhile, Shutdown associates with transposons in the PIWI-interacting RNA pathway, playing a crucial role in both germ cells and ovarian somas. Mutations in or silencing of dFKBPs lead to early embryonic lethality in Drosophila. Therefore, further understanding the mechanisms of FK506 and rapamycin binding to immunophilin FKBPs in endocrine, cardiovascular, and neurological function in both mammals and Drosophila would provide prospects in generating unique, insect specific therapeutics targeting the above cellular signaling pathways. CONCLUSION: This review will evaluate the functional roles of FKBP family proteins, and systematically summarize the similarities and differences between FKBP proteins in Drosophila and Mammals. Specific therapeutics targeting cellular signaling pathways will also be discussed.

Liver-specific NG37 overexpression leads to diet-dependent fatty liver disease accompanied by cardiac dysfunction.

BACKGROUND: Environmental factors are well-known causes of diseases. However, aside from a handful of risk indicators, genes' encoding susceptibility to chronic illnesses and their associated environmental triggers are largely unknown. In this era of increasingly rich diets, such genetic predispositions would be immensely helpful from a public health perspective. The novel transgenic mouse model with liver-specific NG37 overexpression characterized in this article identifies the diet-dependent function of NG37 in the pathogenesis of fatty liver disease and cardiac arrhythmia. RESULTS: The liver-specific NG37 overexpression transgenic mouse model described here was generated using the Alb-SV40 polyA expression plasmid backbone. NG37 cDNA under control of the albumin promoter for liver-specific expression was fused with a 5' terminal M2 FLAG sequence and a SV40 early region transcription terminator/polyadenylation site attached at the 3'-UTR. These NG37 transgenic mice developed normally and were physiologically normal on a standard diet. However, in comparison to non-transgenic (nTG) litter mates, these mice develop dramatic phenotypes within 12-18 days of starting a high-fat diet: (i) increased body weight (28.5 ± 12.3 g), (ii) increased liver weight (87.4 ± 35.7 mg), (iii) increased heart weight (140 ± 38.4 mg), and (iv) cardiac arrhythmia. The enlarged livers of high-fat diet NG37 transgenic mice was histologically similar to human fatty liver disease and contained Maltese cross birefringent active depositions in hepatocytes that are indicative of fatty liver disease. We also confirmed via X-ray diffraction the steatotic vesicles in the diseased hepatocytes of our high-fat diet NG37 mice was composed of cholesteryl derivatives also found in human fatty liver disease. In addition to cardiac enlargement, NG37 transgenic mice on high-fat diet also exhibited highly irregular bradycardia not present in either high-fat diet nTG littermates or normal-diet transgenic litter mates. CONCLUSIONS: The dramatic high-fat diet-dependent symptoms (increased body weight, cardiac enlargement, fatty liver, and cardiac arrhythmias) characterized in our liver-specific NG37 overexpression mouse model identifies NG37 as a gene encoding latent lipid metabolism pathology induced only in the presence of an environmental factor relevant to human health: high-fat diet.

Specific structure and unique function define the hemicentin.

Hemicentin has come a long way from when it was first identified in C. elegans as him-4 (High incidence of males). The protein is now a recognized player in maintaining the architectural integrity of vertebrate tissues and organs. Highly conserved hemicentin sequences across species indicate this gene's ancient evolutionary roots and functional importance. In mouse, hemicentin is liberally distributed on the cell surface of many cell types, including epithelial cells, endothelial cells of the eye, lung, and uterus, and trophectodermal cells of blastocyst. Recent discoveries have uncovered yet another vital purpose of hemicentin 1. The protein also serves a unique function in mitotic cytokinesis, during which this extracellular matrix protein plays a key role in cleavage furrow maturation. Though understanding of hemicentin function has improved through new discoveries, much about this protein remains mysterious.