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Langerhans cell histiocytosis (LCH) is an uncommon clonal proliferation of myeloid progenitor cells, it is especially rare in adults. We present a case of multi-system LCH in a 53-year-old woman, the sole symptom of which was prolonged, non-resolving hip pain for 18 months prior to the diagnosis. Initial evaluation included imaging studies aimed at identifying a presumed local etiology. X-ray demonstrated non-specific arthritic changes on the left femur. Computed tomography (CT) and magnetic resonance imaging (MRI) scans identified a lytic lesion at the same location, warranting a systemic workup. After non-invasive investigations failed to reveal the underlying etiology, a biopsy was performed, revealing cores of Langerhans cells that stained positive for both CD1a and langerin. These findings verified the surprising, uncommon diagnosis of LCH. A comprehensive workup was conducted in order to determine the extent of the disease and its molecular nature - revealing a BRAF V600E -positive, high-risk, multi-system LCH with skeletal, lung and liver involvement., Competing Interests: Declaration of Competing Interest The Authors declare that there is no conflict of interest., (Copyright © 2022 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Current reports concerning cardiac involvement in the novel corona virus disease (COVID-19) mostly document acute myocardial injury at presentation. Here, we present a healthy young male, with presumed acute myocarditis, presenting 20 days after initial diagnosis of COVID-19 - and after a clinical, and apparent laboratory, resolution of the original episode. His sole substantial clinical finding upon admission was fever, which was followed by a witnessed elevation in troponin-I., (Copyright © 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

The endoplasmic reticulum (ER) is a major site for protein synthesis, folding and transport, lipid and steroid synthesis, regulating redox potential, as well as calcium storage. It therefore relies on delicate homeostasis, and perturbation of the ER function and induction of ER stress can lead to apoptosis. One cause of disruption of the ER homeostasis is the accumulation of misfolded proteins. To prevent this perturbation, the Endoplasmic Reticulum-Associated Degradation (ERAD) quality control machinery is recruited to remove these proteins in a three-step process: (1) extraction from the ER, (2) ubiquitination, and (3) subsequent proteasomal degradation. However, the identity of the proteins regulated by the proteasome following induction of the ER stress has remained obscure. In the present study, we investigated the role of the proteasome in the modulation of the proteome of HeLa cells after treatment with thapsigargin and tunicamycin, two drugs known to induce ER stress through accumulation of misfolded proteins. Using label-free quantitative proteomics we found that out of the proteins identified to decrease in their level following induction of ER stress, more than 64% are targeted by the proteasome. Among these proteins, key players of the Wnt signaling pathway, such as β-catenin and GSK3, as well as α-catenin which is involved in cell-cell adhesion, were identified as being modulated by the proteasome upon ER stress., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The proteasome is one of the main catalytic machineries of eukaryotic cells responsible for protein degradation, and is known to be regulated during several cellular stress conditions. Recent studies suggest that the activity of the proteasome is modulated following mTOR inhibition. However, it is not clear how this process affects the proteome. In the present study, we investigated the role of the proteasome in the modulation of the proteome of HeLa cells following amino acid starvation, a stress known to inhibit mTOR activity. We used label-free quantitative proteomics to identify proteins regulated by the proteasome in starved cells. We found that nearly 50% of the proteins the level of which decreased significantly during starvation stress, could be rescued by addition of the proteasome inhibitor MG132. This suggests a key role for the proteasome in reshaping the proteome under starvation. Importantly, the expression of several of these proteins is known to be dependent on the transcription factor E2F1. Further investigation of E2F1 level showed that this transcription factor along with several other proteins involved in its pathway are regulated by the proteasome upon amino acids starvation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Systems analogous to the eukaryotic ubiquitin-proteasome system have been previously identified in Archaea, and Actinobacteria (gram-positive), but not in gram-negative bacteria. Here, we report the bioinformatic identification of a novel prokaryotic ubiquitin-like protein, which we name UBact. The phyletic distribution of UBact covers at least five gram-negative bacterial phyla, including Nitrospirae, Armatimonadetes, Verrucomicroba, Nitrospinae, and Planctomycetes. Additionally, it was identified in seven candidate (uncultured) phyla and one Archaeon. UBact might have been overlooked because only few species in the phyla where it is found have been sequenced. In most of the species where we identified UBact, its neighbors in the genome code for proteins homologous to those involved in conjugation and/or degradation of Pup and Pup-tagged substrates. Among them are PafA-, Dop-, Mpa- and proteasome-homologous proteins. This gene association as well as UBact's size and conserved C-terminal G[E/Q] motif, strongly suggest that UBact is used as a conjugatable tag for degradation. With regard to its C-terminus, UBact differs from ubiquitin and most ubiquitin-like proteins (including the mycobacterial Pup) in that it lacks the characteristic C-terminal di-glycine motif, and it usually ends with the sequence R[T/S]G[E/Q]. The phyla that contain UBact are thought to have diverged over 3000 million years ago, indicating that either this ubiquitin-like conjugation system evolved early in evolution or that its occurrence in distant gram-negative phyla is due to multiple instances of horizontal gene transfer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The living cell is an ever changing, responsive, and adaptive environment where proteins play key roles in all processes and functions. While the scientific community focused for a long time on the decoding of the information required for protein synthesis, little attention was paid to the mechanisms by which proteins are removed from the cell. We now realize that the timely and proper activity of proteins is regulated to a large extent by their degradation; that cellular coping with different physiological cues and stress conditions depends on different catabolic pathways; and that many pathological states result from improper protein breakdown. There are two major protein degradation systems in all eukaryotic cells-the ubiquitin- proteasome and the autophagy-lysosome. The two systems are highly regulated, and-via degradation of a broad array of proteins-are responsible for maintenance of protein homeostasis and adaptation to environmental changes. Each is comprised of numerous components responsible for its coordinated function, and together they encompass a considerable fraction of the entire genome. In this review, we shall discuss the common and diverse characteristics of the ubiquitin-proteasome system (UPS) and autophagy-their substructure, mechanisms of action, function and concerted regulation under varying pathophysiological conditions., (Copyright © 2016 Elsevier Ltd. All rights reserved.)