PNAS Plus Significance Statements

2014 Proceedings of the National Academy of Sciences of the United States of America  
Ferroelectricity has long been speculated to have important biological functions, although its very existence in biology has never been firmly established. Here (pp. E2780-E2786), we present, to our knowledge, the first macroscopic observation of ferroelectric switching in a biological system, and we elucidate the origin and mechanism underpinning ferroelectric switching of elastin. It is discovered that the polarization in elastin is intrinsic at the monomer level, analogous to the unit cell
more » ... to the unit cell level polarization in classical perovskite ferroelectrics. Our findings settle a long-standing question on ferroelectric switching in biology and establish ferroelectricity as an important biophysical property of proteins. We believe this is a critical first step toward resolving its physiological significance and pathological implications. Defense mechanisms against predators, parasites, and pathogens are a hallmark of all multicellular life forms. A conserved defense mechanism is the production of toxic proteins. Because of the limited number of innate defense effectors in a specific host organism, the target epitopes of such toxins are usually highly conserved or occur in different molecular contexts to cover a large spectrum of antagonists. Because glycan epitopes are part of different surface-displayed glycoconjugates in different organisms, carbohydrate-binding proteins (lectins) are the prevailing type of protein toxins in many multicellular organisms. Here (pp. E2787-E2796) we provide evidence that defense lectins can be specific for secondary glycan modifications, such as O-methylation, thereby broadening the range of target organisms. Only a fraction of immature B cells enter the mature B-cell pool to produce antibodies. Autoreactive immature B cells expressing antibodies to self remain in the bone marrow to continue immunoglobulin gene rearrangements and are selected into the periphery only if they eliminate their autoreactive specificity. We show (pp. E2797-E2806) that the rat sarcoma (Ras)-Erk pathway, which leads to the generation of mature B cells, is not constitutively activated in autoreactive immature B cells. Furthermore, activation of Ras can alter the selection pattern of autoreactive cells, inhibiting immunoglobulin gene recombination via PI3K, promoting cell differentiation via Erk, and resulting in secretion of autoantibodies. This suggests that changes in the activation of the Ras-Erk/PI3K pathway have the potential to lead to autoimmune manifestations. Forkhead box P3 + (Foxp3 + ) regulatory T cells (Tregs) are important for maintaining immune homeostasis and tolerance. The pivotal role of Tregs in immune tolerance demands that they possess a dedicated molecular machinery to maintain stable Foxp3 expression when challenged by an inflammatory environment. Whereas epigenetic mechanisms acting on the foxp3 locus have been extensively implicated in Tregs' stable expression of Foxp3, the detailed molecular machinery remains elusive. In this study, we show that methyl-CpG binding protein 2 (MeCP2), an X-linked multifunctional epigenetic regulator, is a crucial player in the epigenetic machinery that confers Tregs with resilience against inflammation. Our study (pp. E2807-E2816) provides, to our knowledge, the first mechanistic description by which MeCP2, a molecule best known for its function in the central nervous system, regulates Treg function and immune tolerance. Mammalian target of rapamycin complex 1 (mTORC1) inhibitors are commonly used as immunosuppressants in solid-organ transplantation and as antiproliferative agents in various cancers. Despite indications of serious renal adverse events caused by mTORC1 inhibition, the role of mTORC1 for renal epithelial function and homeostasis has remained elusive. Unexpectedly, tubular mTORC1 controls energy-driven urine-concentrating mechanisms by maintaining mitochondrial biogenesis. Under pathophysiological conditions, mTORC1-dependent mitochondrial biogenesis is essential for energy supply and adaptation in response to ischemia. These findings (pp. E2817-E2826) identify mTORC1 as an important regulator of tubular energy metabolism, transcellular transport processes, and ischemic stress responses. www.pnas.org/cgi/
doi:10.1073/pnas.ss11127 fatcat:svh5eyz3a5dehaz4kidvxmy3vu