Targeting chaperone modifications: Innovative approaches to cancer treatment

Cancer and other chronic diseases are marked by alterations in the protein quality control system, affecting the post-translational destiny of various proteins that regulate, structure, and catalyze cellular processes. Cellular chaperones, also known as heat shock proteins (HSPs), are pivotal in this system, performing protein triage that often determines the fate of proteins they bind to. Grasping the regulatory mechanisms of HSPs and their associated cofactors is crucial for understanding protein quality control in both healthy and diseased states. Recent research has shed light on the interactions within the protein quality control system and how post-translational modifications (PTMs) govern protein interactions, function, and localization, which can drive or inhibit cell proliferation. This body of work encompasses critical elements of the heat shock response, including Heat Shock Protein 70 (HSP70), Heat Shock Protein 90 (HSP90), Carboxyl-terminus of HSC70 Interacting Protein (CHIP), and Heat Shock Protein Organizing Protein (HOP). This review aims to synthesize these advancements, offering a holistic understanding of the system and its response when commandeered by diseases like cancer. We focus on the mechanistic shift in co-chaperone engagement-transitioning from HOP to CHIP in association with HSP70 and HSP90-which could influence cellular growth and survival pathways. A comprehensive examination of PTM-driven regulation within the protein quality control network is presented, highlighting the roles of activation factors, chaperones, and co-chaperones. Our insights aim to inform new strategies for therapeutically targeting diseases by considering the entire heat shock response system

New insights into bone morphogenetic protein signaling: focus on angiogenesis

The role of bone morphogenetic proteins (BMPs) in vasculogenesis is still not well understood, despite many recent developments in this area of research. In this review, we discuss the most recent studies that identify new critical mechanisms through which BMP signaling acts with a focus on angiogenesis

Die hard: necroptosis and its impact on age-dependent neuroinflammatory diseases

The pro-inflammatory form of cellular death, necroptosis, is critical to age-related pathologies.Necroptosis primarily functions as an antipathogenic and antitumor biological mechanism by triggering inflammatory pathways within rogue cell bodies, resulting in cell death. Several neurodegenerative conditions have hallmarks of necroptosis, suggesting a potential role for this cell death pathway in the pathogenesis of neuroinflammation and neuronal cell death, likely through the release of pro-inflammatory cytokines that perpetuate inflammatory signaling and neurodegeneration. The receptor-interacting protein kinases 1 and 3 (RIPK1/3) signaling cascade is critical to necroptosis regulation; however, the complete mechanism behind necroptotic activation, regulation, and resolution remains incomplete. In cases where necroptosis is disadvantageous, such as neurodegenerative diseases, we lack effective pharmacological suppressors of necroptosis that could mitigate disease progression. Targeting regulatory proteins within the necroptotic signaling pathway has shown promise; however, the need for specific inhibitors limits therapeutic opportunities. This review focuses on necroptosis and its role in neuroinflammation and neurodegeneration in age-dependent disorders. We comprehensively detail the known necroptotic signaling pathways and potential signaling partners and discuss the ongoing therapeutic efforts in targeting and preventing active necroptotic signaling and their relevance to neuroprotection

Brothers and Sisters: Molecular Insights Into Arterial-Venous Heterogeneity

The molecular differences between arteries and veins are genetically predetermined and are evident even before the first embryonic heart beat. Although ephrinB2 and EphB4 are expressed in cells that will ultimately differentiate into arteries and veins respectively, many other genes have been shown to play a significant role in cell fate determination. The expression patterns of ephrinB2 and EphB4 are restricted to arterial-venous boundaries, and Eph/ephrin signaling provides repulsive cues at arterial-venous boundaries that are thought to prevent intermixing of arterial- and venous-fated cells. However, the maintenance of arterial-venous fate is susceptible to some degree of plasticity. Thus, in response to signals from the ambient microenvironment and shear stress, there is flow-mediated intercalation of the arteries and veins that ultimately leads to the formation of a functional, closed-loop circulation. In addition, cells in the blood vessels of each organ undergo epigenetic, morphologic and functional adaptive changes that are specific to the proximate function of their cognate organ(s). These adaptive changes result in an inter-organ and intra-organ vessel heterogeneity that manifest clinically in a disparate response of different organs to identical risk factors and injury in the same animal. In this review, we will focus on the molecular and physiologic factors influencing arterial-venous heterogeneity between and within different organ(s). We will explore arterial-venous differences in selected organs as well as their respective endothelial cell architectural organization that results in their inter- and intra-organ heterogeneity

Tear Me Down: Role of Calpain in the Development of Cardiac Ventricular Hypertrophy

Cardiac hypertrophy develops most commonly in response to hypertension and is an independent risk factor for the development of heart failure. The mechanisms by which cardiac hypertrophy may be reversed to reduce this risk have not been fully determined to the point where mechanism-specific therapies have been developed. Recently, proteases in the calpain family have been implicated in regulating the development of cardiac hypertrophy in preclinical animal models. In this review, we summarize the molecular mechanisms by which calpain inhibition has been shown to modulate the development of cardiac (specifically ventricular) hypertrophy. The context within which calpain inhibition might be developed for therapeutic intervention of cardiac hypertrophy is then discussed

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

The muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) is critical in regulating both pathological and physiological cardiac hypertrophy in vivo. Previous work from our group has identified MuRF1's ability to inhibit serum response factor and insulin-like growth factor-1 signaling pathways (via targeted inhibition of cJun as underlying mechanisms). More recently, we have identified that MuRF1 inhibits fatty acid metabolism by targeting peroxisome proliferator-activated receptor alpha (PPARα) for nuclear export via mono-ubiquitination. Since MuRF1−/− mice have an estimated fivefold increase in PPARα activity, we sought to determine how challenge with the PPARα agonist fenofibrate, a PPARα ligand, would affect the heart physiologically. In as little as 3 weeks, feeding with fenofibrate/chow (0.05% wt/wt) induced unexpected pathological cardiac hypertrophy not present in age-matched sibling wild-type (MuRF1 +/+) mice, identified by echocardiography, cardiomyocyte cross-sectional area, and increased beta-myosin heavy chain, brain natriuretic peptide, and skeletal muscle α-actin mRNA. In addition to pathological hypertrophy, MuRF1−/− mice had an unexpected differential expression in genes associated with the pleiotropic effects of fenofibrate involved in the extracellular matrix, protease inhibition, hemostasis, and the sarcomere. At both 3 and 8 weeks of fenofibrate treatment, the differentially expressed MuRF1−/− genes most commonly had SREBP-1 and E2F1/E2F promoter regions by TRANSFAC analysis (54 and 50 genes, respectively, of the 111 of the genes >4 and <−4 log fold change; P≤.0004). These studies identify MuRF1's unexpected regulation of fenofibrate's pleiotropic effects and bridges, for the first time, MuRF1's regulation of PPARα, cardiac hypertrophy, and hemostasis

CHIP protects against cardiac pressure overload through regulation of AMPK

Protein quality control and metabolic homeostasis are integral to maintaining cardiac function during stress; however, little is known about if or how these systems interact. Here we demonstrate that C terminus of HSC70-interacting protein (CHIP), a regulator of protein quality control, influences the metabolic response to pressure overload by direct regulation of the catalytic α subunit of AMPK. Induction of cardiac pressure overload in Chip–/– mice resulted in robust hypertrophy and decreased cardiac function and energy generation stemming from a failure to activate AMPK. Mechanistically, CHIP promoted LKB1-mediated phosphorylation of AMPK, increased the specific activity of AMPK, and was necessary and sufficient for stress-dependent activation of AMPK. CHIP-dependent effects on AMPK activity were accompanied by conformational changes specific to the α subunit, both in vitro and in vivo, identifying AMPK as the first physiological substrate for CHIP chaperone activity and establishing a link between cardiac proteolytic and metabolic pathways

Endothelial inflammatory transcriptional responses to an altered plasma exposome following inhalation of diesel emissions

Air pollution, especially emissions derived from traffic sources, is associated with adverse cardiovascular outcomes. However, it remains unclear how inhaled factors drive extrapulmonary pathology

Human amylin proteotoxicity impairs protein biosynthesis, and alters major cellular signaling pathways in the heart, brain and liver of humanized diabetic rat model in vivo

Chronic hypersecretion of the 37 amino acid amylin is common in type 2 diabetics (T2D). Recent studies implicate human amylin aggregates cause proteotoxicity (cell death induced by misfolded proteins) in both the brain and the heart

Cardiac Muscle Ring Finger-1 Increases Susceptibility to Heart Failure In Vivo

Muscle ring finger-1 (MuRF1) is a muscle-specific protein implicated in the regulation of cardiac myocyte size and contractility. MuRF2, a closely related family member, redundantly interacts with protein substrates, and hetero-dimerizes with MuRF1. Mice lacking either MuRF1 or MuRF2 are phenotypically normal whereas mice lacking both proteins develop a spontaneous cardiac and skeletal muscle hypertrophy indicating cooperative control of muscle mass by MuRF1 and MuRF2. In order to identify the unique role that MuRF1 plays in regulating cardiac hypertrophy in vivo, we created transgenic mice expressing increased amounts of cardiac MuRF1. Adult MuRF1 transgenic (Tg+) hearts exhibited a non-progressive thinning of the left ventricular wall and a concomitant decrease in cardiac function. Experimental induction of cardiac hypertrophy by trans-aortic constriction (TAC) induced rapid failure of MuRF1 Tg+ hearts. Microarray analysis identified that the levels of genes associated with metabolism (and in particular mitochondrial processes) were significantly altered in MuRF1 Tg+ hearts, both at baseline and during the development of cardiac hypertrophy. Surprisingly, ATP levels in MuRF1 Tg+ mice did not differ from wild type mice despite the depressed contractility following TAC. In comparing the level and activity of creatine kinase (CK) between wild type and MuRF1 Tg+ hearts we found that mCK and CK-M/B protein levels were unaffected in MuRF1 Tg+ hearts, however total CK activity was significantly inhibited. We conclude that increased expression of cardiac MuRF1 results in a broad disruption of primary metabolic functions, including alterations in CK activity that leads to increased susceptibility to heart failure following TAC. This study demonstrates for the first time a role for MuRF1 in the regulation of cardiac energetics in vivo