The proteasome biogenesis regulator Rpn4 cooperates with the unfolded protein response to promote ER stress resistance

Misfolded proteins in the endoplasmic reticulum (ER) activate the unfolded protein response (U PR), which enhances protein folding to restore homeostasis. Additional pathways respond to ER stress, but how they help counteract protein misfolding is incompletely understood. Here, we develop a titratable system for the induction of ER stress in yeast to enable a genetic screen for factors that augment stress resistance independently of the UPR. We identify the proteasome biogenesis regulator Rpn4 and show that it cooperates with the UPR. Rpn4 abundance increases during ER stress, first by a post-transcriptional, then by a transcriptional mechanism. Induction of RPN4 transcription is triggered by cytosolic mislocalization of secretory proteins, is mediated by multiple signaling pathways and accelerates clearance of misfolded proteins from the cytosol. Thus, Rpn4 and the UPR are complementary elements of a modular cross-compartment response to ER stress

SHRED is a regulatory cascade that reprograms Ubr1 substrate specificity for enhanced protein quality control during stress. Szoradi et al. 2018

This dataset includes raw blot and microscopy images from the manuscript "SHRED is a regulatory cascade that reprograms Ubr1 substrate specificity for enhanced protein quality control during stress" submitted to Molecular Cell. The areas of importance, that were cropped for the original figures in the manuscript, are marked with a box

Polymethyl Methacrylate Bone Cement Polymerization Induced Thermal Necrosis at the Cement–Bone Interface: A Narrative Review

Polymethyl methacrylate (PMMA) bone cement has been a transformative material in orthopedics since its introduction in the mid-20th century. Originally used in dental medicine, PMMA was adopted for orthopedic applications by Sir John Charnley in the 1950s, significantly enhancing joint replacement surgeries. The primary appeal of PMMA lies in its biocompatibility, mechanical strength, and ease of handling, making it a favored choice for various orthopedic procedures, including arthroplasties and limb-salvage surgeries. However, the exothermic polymerization process of PMMA poses a risk of thermal necrosis in the surrounding bone tissue, as local temperatures can exceed 70 °C, causing damage to osteocytes. Research has sought to mitigate these risks by optimizing mixing techniques, reducing cement mantle thickness, and incorporating cooling methods. Recent advancements, such as the use of phase-change materials (PCMs) and alternative monomers, have shown promise in lowering the exothermic peak during polymerization. Other strategies include pre-cooling the cement and prosthetic components and using composite cement. Despite these innovations, managing the balance between minimizing heat generation and maintaining mechanical properties remains a challenge. The impact of thermal necrosis is significant, compromising implant stability and osseointegration. Understanding the complex interactions between PMMA’s thermal properties and its clinical outcomes is essential for improving orthopedic surgical practices and patient recovery

SHRED Is a Regulatory Cascade that Reprograms Ubr1 Substrate Specificity for Enhanced Protein Quality Control during Stress

When faced with proteotoxic stress, cells mount adaptive responses to eliminate aberrant proteins. Adaptive responses increase the expression of protein folding and degradation factors to enhance the cellular quality control machinery. However, it is unclear whether and how this augmented machinery acquires new activities during stress. Here, we uncover a regulatory cascade in budding yeast that consists of the hydrophilin protein Roq1/Yjl144w, the HtrA-type protease Ynm3/Nma111, and the ubiquitin ligase Ubr1. Various stresses stimulate ROQ1 transcription. The Roq1 protein is cleaved by Ynm3. Cleaved Roq1 interacts with Ubr1, transforming its substrate specificity. Altered substrate recognition by Ubr1 accelerates proteasomal degradation of misfolded as well as native proteins at the endoplasmic reticulum membrane and in the cytosol. We term this pathway stress-induced homeostatically regulated protein degradation (SHRED) and propose that it promotes physiological adaptation by reprogramming a key component of the quality control machinery