Life and destruction: ubiquitin-mediated proteolysis in aging and longevity

The ubiquitin/proteasome system (UPS) regulates the turnover of improperly folded and damaged proteins to maintain protein homeostasis (proteostasis), cellular function, and viability. It is commonly thought that an age-related impairment of the UPS affects general proteostasis networks, which causes enhanced protein aggregation and contributes to normal aging. Recent studies identified the existence of ubiquitin-dependent degradation pathways that specifically control lifespan regulators, suggesting additional roles for ubiquitylation in aging and longevity

Double-edged alliance: mitochondrial surveillance by the UPS and autophagy

Mitochondria provide an essential role in the maintenance of cellular homeostasis with regard to energy generation, redox signaling, and programmed cell death. Consequently, fast adaptation to metabolic changes associated with developmental demands or stress induction requires a balanced coordination of mitochondrial biogenesis and removal of damaged mitochondria. Impaired mitochondrial maintenance is causally linked to many human pathologies and aging, including diabetes, cancer, and neurodegenerative diseases. Thus, it is of fundamental importance to understand cellular surveillance mechanisms that support a healthy mitochondrial network. In this review, we discuss the role of ubiquitin-dependent protein degradation in mitochondrial functionality

Strategic complementarity and substitutability of investment strategies

Investors in equities tend to follow well-defined investment strategies based on characteristics such as market capitalization and dividend yield or factors such as size, value, momentum and quality which capture the cross-section of asset returns. In this paper, we explore the interaction of such investment strategies in a demand-driven framework. The aim is to quantify the impact of a reallocation of capital between strategies on the cross-section of their performance. The main finding is that self- and cross-impact caused by the reallocation of capital can explain capacity of strategies, correlation of returns and the cyclical nature of investment strategies’ risk premia

Two novel ADAMTS13 gene mutations in thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS)

Two novel ADAMTS13 gene mutations in thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS).BackgroundThrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are now considered to be variants of one single syndrome called thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). Key features are thrombocytopenia, hemolytic anemia, and subsequently impaired function of different organs, especially the kidneys and the central nervous system (CNS). One possible reason is the deficiency of von Willebrand factor-cleaving protease (vWF-CP) resulting in persistence of uncleaved, ultralarge von Willebrand factor multimers (ULvWFM).MethodsWe report a patient who was initially diagnosed with Evans syndrome (hemolytic anemia and autoimmune thrombocytopenia) as infant. At 10 years of age he developed HUS-like disease with gastrointestinal tract infection, hemolytic anemia, thrombocytopenia,and acute renal failure. However, enteropathogenic Escherichia coli–like or Shiga-like toxins were not detected.ResultsFurther investigations revealed severe deficiency (<3%; normal >40%) of vWF-CP activity caused by compound heterozygosity of two novel ADAMTS13 gene mutations (1170 G>C [W390C] and 3735 G>A [W1245X]. vWF-CP autoantibodies were not detected. Periodic (every 2 weeks) treatment with fresh frozen plasma (FFP) maintained both platelet level and kidney function within normal range and prevented new episodes of TTP/HUS.ConclusionEnteropathogenic E. coli– and Shiga-like toxin-negative patients who present with hemolytic or thrombocytopenic episodes and HUS like symptoms should be tested for vWF-CP deficiency and other noninfectious reasons for TTP/HUS since plasma substitution possibly provides an efficient therapeutic option for this subgroup of patients

USP7 and VCP define the SUMO/Ubiquitin landscape at the DNA replication fork

The AAA+ ATPase VCP regulates the extraction of SUMO and ubiquitin-modified DNA replication factors from chromatin. We have previously described that active DNA synthesis is associated with a SUMO-high/ubiquitin-low environment governed by the deubiquitylase USP7. Here, we unveil a functional cooperation between USP7 and VCP in DNA replication, which is conserved from Caenorhabditis elegans to mammals. The role of VCP in chromatin is defined by its cofactor FAF1, which facilitates the extraction of SUMOylated and ubiquitylated proteins that accumulate after the block of DNA replication in the absence of USP7. The inactivation of USP7 and FAF1 is synthetically lethal both in C. elegans and mammalian cells. In addition, USP7 and VCP inhibitors display synergistic toxicity supporting a functional link between deubiquitylation and extraction of chromatin-bound proteins. Our results suggest that USP7 and VCPFAF1 facilitate DNA replication by controlling the balance of SUMO/Ubiquitin-modified DNA replication factors on chromatinMINECO (BFU2014-55168-JIN; RTI2018-093485-B-I00) and a Ramo´ n y Cajal Fellowship from MINECO (RYC-2016-20705), co-funded by European Regional Development Funds (FEDER) to E.L.; by grants from the Spanish Ministry of Science, Innovation and Universities (RTI2018-102204-B-I00, co-financed with European FEDER funds) and the European Research Council (ERC-617840) to O.F.-C.; fellowships from Fundacion Ramón Areces-UAM and La Caixa Foundation to P.V. (LCF/BQ/ES18/11670008

The ubiquitin ligase CHIP integrates proteostasis and aging by regulation of insulin receptor turnover

Aging is attended by a progressive decline in protein homeostasis (proteostasis), aggravating the risk for protein aggregation diseases. To understand the coordination between proteome imbalance and longevity, we addressed the mechanistic role of the quality-control ubiquitin ligase CHIP, which is a key regulator of proteostasis. We observed that CHIP deficiency leads to increased levels of the insulin receptor (INSR) and reduced lifespan of worms and flies. The membrane-bound INSR regulates the insulin and IGF1 signaling (IIS) pathway and thereby defines metabolism and aging. INSR is a direct target of CHIP, which triggers receptor monoubiquitylation and endocytic-lysosomal turnover to promote longevity. However, upon proteotoxic stress conditions and during aging, CHIP is recruited toward disposal of misfolded proteins, reducing its capacity to degrade the INSR. Our study indicates a competitive relationship between proteostasis and longevity regulation through CHIP-assisted proteolysis, providing a mechanistic concept for understanding the impact of proteome imbalance on aging

Ubiquitin sets the timer: impacts on aging and longevity

Protein homeostasis is essential for cellular function, organismal growth and viability. Damaged and aggregated proteins are turned over by two major proteolytic routes of the cellular quality-control pathways: the ubiquitin-proteasome system and autophagy. For both these pathways, ubiquitination provides the recognition signal for substrate selection. This Commentary discusses how ubiquitin-dependent proteolytic pathways are coordinated with stress- and aging-induced signals

E4 ligase–specific ubiquitination hubs coordinate DNA double-strand-break repair and apoptosis

Multiple protein ubiquitination events at DNA double-strand breaks (DSBs) regulate damage recognition, signaling and repair. It has remained poorly understood how the repair process of DSBs is coordinated with the apoptotic response. Here, we identified the E4 ubiquitin ligase UFD-2 as a mediator of DNA-damage-induced apoptosis in a genetic screen in Caenorhabditis elegans. We found that, after initiation of homologous recombination by RAD-51, UFD-2 forms foci that contain substrate-processivity factors including the ubiquitin-selective segregase CDC-48 (p97), the deubiquitination enzyme ATX-3 (Ataxin-3) and the proteasome. In the absence of UFD-2, RAD-51 foci persist, and DNA damage-induced apoptosis is prevented. In contrast, UFD-2 foci are retained until recombination intermediates are removed by the Holliday-junction-processing enzymes GEN-1, MUS-81 or XPF-1. Formation of UFD-2 foci also requires proapoptotic CEP-1 (p53) signaling. Our findings establish a central role of UFD-2 in the coordination between the DNA-repair process and the apoptotic response