From Drosophila to Humans: Reflections on the Roles of the Prolyl Isomerases and Chaperones, Cyclophilins, in Cell Function and Disease

Abstract

Abstract: Despite remarkable advances in human genetics and other genetic model systems, the fruit fly, Drosophila melanogaster, remains a powerful experimental tool to probe with ease the inner workings of a myriad of biological and pathological processes, even when evolutionary forces impart apparent divergences to some of such processes. The understanding of such evolutionary differences provides mechanistic insights into genotype-phenotype correlations underpinning biological processes across metazoans. The pioneering work developed by the William Pak laboratory for the past four decades, and the work of others, epitomize the notion of how the Drosophila system breaks new fertile ground or complements research fields of high scientific and medical relevance. Among the three major genetic complementation groups produced by the Pak's laboratory and impairing distinct facets of photoreceptor neuronal function, the nina group (ninaA, …., ninaJ) selectively affects the biogenesis of G protein–coupled receptors (GPCRs), mediating the photoconversion and transduction of light stimuli. Among the nina genes identified, ninaA arguably assumes heightened significance for several reasons. First, it presents unique physiological selectivity toward the biogenesis of a subset of GPCRs, a standalone biological manifestation yet to be discerned for most mammalian homologues of NinaA. Second, NinaA belongs to a family of proteins, immunophilins, which are the primary targets for immunosuppressive drugs at the therapeutic forefront of a multitude of medical conditions. Third, NinaA closest homologue, cyclophilin B (CyPB/PPIB), is an immunophilin whose loss-of-function was found recently to cause osteogenesis imperfecta in the human. This report highlights advances made by studies on some members of immunophilins, the cyclophilins. Finally, it reexamines critically data and dogmas derived from past and recent genetic, structural, biological, and pathological studies on NinaA and few other cyclophilins that support some of such paradigms to be less than definite and advance our understanding of the roles of cyclophilins in cell function, disease, and therapeutic interventions.

Keywords::

• ninaA
• cyclophilin
• chaperone
• proly isomerase
• cyclosporin A (CsA)
• immunophilin
• protein biogenesis

ACKNOWLEDGMENTS

We thank members of the Ferreira laboratory for critically reading the manuscript. This work was supported by grants from the National Institutes of Health to P.A.F. (EY019492, GM083165). P.A.F. is the Jules & Doris Stein Research to Prevent Blindness Professor.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.