Protein accumulation is a hallmark of many neurodegenerative disorders. In Alzheimer’s disease (AD), a hyperphosphorylated form of the protein tau (p-tau) forms intracellular inclusions known as neurofibrillary tangles. Deposits of p-tau have also been found in the brains of patients with Down’s syndrome, supranuclear palsy, and prion disease. Mutations in tau have been causally associated with at least one inherited neurologic disorder, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), implying that tau abnormalities by themselves can be a primary cause of degenerative diseases of the CNS. Removal of these p-tau species may occur by both chaperone-mediated refolding and degradation. In this issue of the JCI, Dickey and colleagues show that a cochaperone protein, carboxyl terminus of Hsp70-interacting protein (CHIP), in a complex with Hsp90 plays an important role in the removal of p-tau (see the related article beginning on page 648). Pharmacologic manipulation of Hsp90 may be used to alleviate p-tau accumulation in disease.
Dmitry Goryunov, Ronald K.H. Liem
The hormone aldosterone increases extracellular fluid volume and blood pressure by activating epithelial Na+ channels (ENaCs). Serum- and glucocorticoid-induced kinase 1 (SGK1) is an aldosterone-stimulated signaling molecule that enhances distal nephron Na+ transport, in part by preventing the internalization of ENaCs from the plasma membrane. In this issue of the JCI, Zhang et al. demonstrate that SGK1 enhances transcription of the α subunit of ENaC by preventing histone methylation, providing an additional mechanism by which SGK1 increases ENaC-mediated Na+ transport in the distal nephron (see the related article beginning on page 773).
David Pearce, Thomas R. Kleyman
Inhaled environmental oxidants, such as ozone and particulates, have been variably linked to epithelial injury, inflammation, and perturbations in lung development, growth, and function. Reactions between ozone and lung surface lipids likely account for exposure-related pathophysiologic sequelae. In this issue of the JCI, Dahl et al. document a previously unrecognized pulmonary defense against inhaled oxidants in mice: macrophage scavenger receptors (SRs) bind proinflammatory oxidized lipids, thereby decreasing pulmonary inflammation (see the related article beginning on page 757). The study adds to our knowledge of diverse lung oxidative processes and identifies a potential regulatory mechanism governing pulmonary inflammation. Further investigations to elucidate more precise mechanisms and to determine the influence of SRs on airway epithelial injury, repair, and remodeling are warranted.
Edward M. Postlethwait
Natural antibodies are autoreactive/polyreactive antibodies believed to be secreted in the absence of xenoantigens. The origin and functional role of this limited and selective autoimmunity are not clear, nor is the specificity and range of autoantigens that drive the development of B cells producing natural antibodies. In this issue of the JCI, Merbl et al. report that in utero, humans generate natural IgM and IgA antibodies that recognize a uniform set of autoantigens (see the related article beginning on page 712), some of which are associated with autoimmune diseases. The authors postulate that this “autoimmunity” at birth favors the emergence of autoimmune diseases in later life. We present a molecular basis for the limited and common repertoire of antibodies produced by fetal B cells, which may be distinct from the abnormalities in B cell development described in patients with autoimmune diseases.
Eric Meffre, Jane E. Salmon
In this issue of the JCI, Vaisar et al. studied the proteome of HDL (see the related article beginning on page 746). They reveal, quite unexpectedly, that HDL is enriched in several proteins involved in the complement cascade, as well as in a variety of protease inhibitors, supporting the concept that HDL plays a role in innate immunity and in the regulation of proteolytic cascades involved in inflammatory and coagulation processes. The protein makeup of HDL also appears to be altered in patients with coronary artery disease. HDL proteomics is in its infancy, and preliminary findings will need to be confirmed using standardized approaches in larger clinical samples. However, this approach promises to better elucidate the relationship of HDL to atherosclerosis and its complications and could eventually help in the development of biomarkers to predict the outcome of interventions that alter HDL levels and functions.
Muredach P. Reilly, Alan R. Tall
The combination of the induction of lymphopenia and vaccination and/or T cell transfer is garnering much attention for cancer treatment. Preclinical studies have shown that the induction of lymphopenia by chemotherapy or radiation can enhance the antitumor efficacy of several distinct, cell-based immunotherapeutic approaches. The mechanism(s) by which such enhancement is achieved are being intensively studied, yet there is much opportunity for improvement. The animal studies reported by Wrzesinski and colleagues in this issue of the JCI are a promising and timely step in this direction (see the related article beginning on page 492). The authors have evaluated both the effect of increasing the intensity of lymphodepletion and the influence of HSC transfer on the in vivo function of adoptively transferred CD8+ T cells. We discuss their results in light of the evolving field and their implications for advancing cell-based immunotherapies for cancer.
Claudio Anasetti, James J. Mulé
It has become increasingly obvious that the notion of a terminally differentiated cell is likely a simplified concept. Epithelial-mesenchymal transition (EMT), during which epithelial cells assume a mesenchymal phenotype, is a key event occurring during normal development and pathological processes. Multiple extracellular stimuli and transcriptional regulators can trigger EMT, but how such distinct signaling pathways orchestrate the complex cellular events that facilitate EMT is not well understood. In this issue of the JCI, Venkov et al. report on their examination of fibroblasts resulting from EMT and describe a novel protein-DNA complex that is essential for transcription of fibroblast-specific protein 1 (FSP1) and sufficient to induce early EMT events (see the related article beginning on page 482). Collectively, their results suggest that this complex is an important regulator of the EMT transcriptome.
Yingqi Teng, Michael Zeisberg, Raghu Kalluri
The exact role(s) of the cytokine IFN-γ in the demyelinating disease multiple sclerosis remain controversial, with evidence suggesting both detrimental and protective effects of the cytokine in MS and MS models such as EAE. The study by Lin and coworkers in this issue of the JCI produces evidence that protective effects of IFN-γ on mature oligodendrocytes during EAE induction are mediated via activation of the pancreatic ER kinase (PERK), resulting in induction of the endoplasmic reticular stress response pathway (see the related article beginning on page 448). Modulation of this stress pathway has what we believe to be novel therapeutic potential for MS.
Jason R. Lees, Anne H. Cross
The way in which multiple cell types organize themselves into a carefully sculpted, 3D labyrinth of vessels that regulate blood flow throughout the body has been a longstanding mystery. Clinicians familiar with congenital cardiovascular disease recognize how genetic variants and modest perturbations in this complex set of spatiotemporal interactions and stochastic processes can result in life-threatening anomalies. Although the mystery is not yet fully solved, we are poised at an exciting juncture, as insights from murine disease models are converging with advances in human genetics to shed new light on puzzling clinical phenotypes of vascular disease. The study by High et al. in this issue of the JCI establishes a model system that mimics clinical features of congenital cardiovascular disease and further defines the role of the Notch signaling pathway in the neural crest as an essential determinant of cardiovascular structure (see the related article beginning on page 353).
Leonard M. Anderson, Gary H. Gibbons
Nutrient overload induces obesity, a primary risk factor for type 2 diabetes. Ribosomal biogenesis and protein synthesis, which are controlled by the mammalian target of rapamycin (mTOR), are primary energy-consuming processes in cells. mTOR phosphorylates and inactivates members of the eukaryotic translation initiation factor 4E–binding (eIF4E-binding) protein (4E-BP) family, which are translational repressors of 5′ cap–dependent protein synthesis. In this issue of the JCI, Le Bacquer et al. report that simultaneous deletion of both 4E-BP1 and 4E-BP2 in mice results in insulin resistance, decreased energy expenditure, and increased adipogenesis (see the related article beginning on page 387). These findings link protein synthesis, insulin sensitivity, and body weight.
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