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Annual Review of Pathology Jan 2024Dystonia is a clinically and genetically highly heterogeneous neurological disorder characterized by abnormal movements and postures caused by involuntary sustained or... (Review)
Review
Dystonia is a clinically and genetically highly heterogeneous neurological disorder characterized by abnormal movements and postures caused by involuntary sustained or intermittent muscle contractions. A number of groundbreaking genetic and molecular insights have recently been gained. While they enable genetic testing and counseling, their translation into new therapies is still limited. However, we are beginning to understand shared pathophysiological pathways and molecular mechanisms. It has become clear that dystonia results from a dysfunctional network involving the basal ganglia, cerebellum, thalamus, and cortex. On the molecular level, more than a handful of, often intertwined, pathways have been linked to pathogenic variants in dystonia genes, including gene transcription during neurodevelopment (e.g., , ), calcium homeostasis (e.g., , ), striatal dopamine signaling (e.g., ), endoplasmic reticulum stress response (e.g., , , ), autophagy (e.g., ), and others. Thus, different forms of dystonia can be molecularly grouped, which may facilitate treatment development in the future.
Topics: Humans; Dystonia; Dystonic Disorders; Dopamine; Molecular Chaperones; DNA-Binding Proteins; Apoptosis Regulatory Proteins; Anoctamins
PubMed: 37738511
DOI: 10.1146/annurev-pathmechdis-051122-110756 -
Science (New York, N.Y.) Aug 2023The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require...
The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product-inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRAS (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRAS tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRAS or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).
Topics: Humans; Biological Products; Cysteine; Molecular Chaperones; Proto-Oncogene Proteins p21(ras); Signal Transduction; Cyclophilin A; Immunophilins; Neoplasms
PubMed: 37590355
DOI: 10.1126/science.adg9652 -
Nature Reviews. Molecular Cell Biology Dec 2023Despite advances in machine learning-based protein structure prediction, we are still far from fully understanding how proteins fold into their native conformation. The... (Review)
Review
Despite advances in machine learning-based protein structure prediction, we are still far from fully understanding how proteins fold into their native conformation. The conventional notion that polypeptides fold spontaneously to their biologically active states has gradually been replaced by our understanding that cellular protein folding often requires context-dependent guidance from molecular chaperones in order to avoid misfolding. Misfolded proteins can aggregate into larger structures, such as amyloid fibrils, which perpetuate the misfolding process, creating a self-reinforcing cascade. A surge in amyloid fibril structures has deepened our comprehension of how a single polypeptide sequence can exhibit multiple amyloid conformations, known as polymorphism. The assembly of these polymorphs is not a random process but is influenced by the specific conditions and tissues in which they originate. This observation suggests that, similar to the folding of native proteins, the kinetics of pathological amyloid assembly are modulated by interactions specific to cells and tissues. Here, we review the current understanding of how intrinsic protein conformational propensities are modulated by physiological and pathological interactions in the cell to shape protein misfolding and aggregation pathology.
Topics: Protein Conformation; Protein Folding; Amyloid; Peptides; Molecular Chaperones
PubMed: 37684425
DOI: 10.1038/s41580-023-00647-2 -
Nature Reviews. Molecular Cell Biology Nov 2023Heat shock protein 90 (HSP90) is a chaperone with vital roles in regulating proteostasis, long recognized for its function in protein folding and maturation. A view is... (Review)
Review
Heat shock protein 90 (HSP90) is a chaperone with vital roles in regulating proteostasis, long recognized for its function in protein folding and maturation. A view is emerging that identifies HSP90 not as one protein that is structurally and functionally homogeneous but, rather, as a protein that is shaped by its environment. In this Review, we discuss evidence of multiple structural forms of HSP90 in health and disease, including homo-oligomers and hetero-oligomers, also termed epichaperomes, and examine the impact of stress, post-translational modifications and co-chaperones on their formation. We describe how these variations influence context-dependent functions of HSP90 as well as its interaction with other chaperones, co-chaperones and proteins, and how this structural complexity of HSP90 impacts and is impacted by its interaction with small molecule modulators. We close by discussing recent developments regarding the use of HSP90 inhibitors in cancer and how our new appreciation of the structural and functional heterogeneity of HSP90 invites a re-evaluation of how we discover and implement HSP90 therapeutics for disease treatment.
Topics: HSP90 Heat-Shock Proteins; Molecular Chaperones; Protein Folding; Proteostasis; Homeostasis
PubMed: 37524848
DOI: 10.1038/s41580-023-00640-9 -
Clusterin Neutralizes the Inflammatory and Cytotoxic Properties of Extracellular Histones in Sepsis.American Journal of Respiratory and... Jul 2023Extracellular histones, released into the surrounding environment during extensive cell death, promote inflammation and cell death, and these deleterious roles have...
Extracellular histones, released into the surrounding environment during extensive cell death, promote inflammation and cell death, and these deleterious roles have been well documented in sepsis. Clusterin (CLU) is a ubiquitous extracellular protein that chaperones misfolded proteins and promotes their removal. We investigated whether CLU could protect against the deleterious properties of histones. We assessed CLU and histone expression in patients with sepsis and evaluated the protective role of CLU against histones in assays and models of experimental sepsis. We show that CLU binds to circulating histones and reduces their inflammatory, thrombotic, and cytotoxic properties. We observed that plasma CLU levels decreased in patients with sepsis and that the decrease was greater and more durable in nonsurvivors than in survivors. Accordingly, CLU deficiency was associated with increased mortality in mouse models of sepsis and endotoxemia. Finally, CLU supplementation improved mouse survival in a sepsis model. This study identifies CLU as a central endogenous histone-neutralizing molecule and suggests that, in pathologies with extensive cell death, CLU supplementation may improve disease tolerance and host survival.
Topics: Animals; Mice; Histones; Clusterin; Inflammation; Cell Death; Antineoplastic Agents; Sepsis
PubMed: 37141109
DOI: 10.1164/rccm.202207-1253OC -
Cell Death & Disease Jul 2023Chemoresistance is one of the major causes of therapeutic failure and poor prognosis for breast cancer patients, especially for triple-negative breast cancer patients....
Chemoresistance is one of the major causes of therapeutic failure and poor prognosis for breast cancer patients, especially for triple-negative breast cancer patients. However, the underlying mechanism remains elusive. Here, we identified novel functional roles of heat shock protein beta-1 (HSPB1), regulating chemoresistance and ferroptotic cell death in breast cancer. Based on TCGA and GEO databases, HSPB1 expression was upregulated in breast cancer tissues and associated with poor prognosis of breast cancer patients, which was considered an independent prognostic factor for breast cancer. Functional assays revealed that HSPB1 could promote cancer growth and metastasis in vitro and in vivo. Furthermore, HSPB1 facilitated doxorubicin (DOX) resistance through protecting breast cancer cells from drug-induced ferroptosis. Mechanistically, HSPB1 could bind with Ikβ-α and promote its ubiquitination-mediated degradation, leading to increased nuclear translocation and activation of NF-κB signaling. In addition, HSPB1 overexpression led to enhanced secretion of IL6, which further facilitated breast cancer progression. These findings revealed that HSPB1 upregulation might be a key driver to progression and chemoresistance through regulating ferroptosis in breast cancer while targeting HSPB1 could be an effective strategy against breast cancer.
Topics: Humans; Female; NF-kappa B; Breast Neoplasms; HSP27 Heat-Shock Proteins; Drug Resistance, Neoplasm; Signal Transduction; Cell Death; Triple Negative Breast Neoplasms; Cell Line, Tumor; Heat-Shock Proteins; Molecular Chaperones
PubMed: 37454220
DOI: 10.1038/s41419-023-05972-0 -
Nature Communications Aug 2023Molecular chaperone HSP70s are attractive targets for cancer therapy, but their substrate broadness and functional non-specificity have limited their role in...
Molecular chaperone HSP70s are attractive targets for cancer therapy, but their substrate broadness and functional non-specificity have limited their role in therapeutical success. Functioning as HSP70's cochaperones, HSP40s determine the client specificity of HSP70s, and could be better targets for cancer therapy. Here we show that tumors defective in HSP40 member DNAJA2 are benefitted from immune-checkpoint blockade (ICB) therapy. Mechanistically, DNAJA2 maintains centrosome homeostasis by timely degrading key centriolar satellite proteins PCM1 and CEP290 via HSC70 chaperone-mediated autophagy (CMA). Tumor cells depleted of DNAJA2 or CMA factor LAMP2A exhibit elevated levels of centriolar satellite proteins, which causes aberrant mitosis characterized by abnormal spindles, chromosome missegregation and micronuclei formation. This activates the cGAS-STING pathway to enhance ICB therapy response in tumors derived from DNAJA2-deficient cells. Our study reveals a role for DNAJA2 to regulate mitotic division and chromosome stability and suggests DNAJA2 as a potential target to enhance cancer immunotherapy, thereby providing strategies to advance HSPs-based cancer therapy.
Topics: Humans; Mitosis; Cell Nucleus Division; Chromogranin A; Nucleotidyltransferases; Chromosomal Instability; HSP70 Heat-Shock Proteins; HSP40 Heat-Shock Proteins
PubMed: 37640708
DOI: 10.1038/s41467-023-40952-0 -
Cell Reports Dec 2023Chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI) are pathways for selective degradation of cytosolic proteins in lysosomes and late endosomes,...
Chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI) are pathways for selective degradation of cytosolic proteins in lysosomes and late endosomes, respectively. These autophagic processes share as a first step the recognition of the same five-amino-acid motif in substrate proteins by the Hsc70 chaperone, raising the possibility of coordinated activity of both pathways. In this work, we show the existence of a compensatory relationship between CMA and eMI and identify a role for the chaperone protein Bag6 in triage and internalization of eMI substrates into late endosomes. Association and dynamics of Bag6 at the late endosome membrane change during starvation, a stressor that, contrary to other autophagic pathways, causes a decline in eMI activity. Collectively, these results show a coordinated function of eMI with CMA, identify the interchangeable subproteome degraded by these pathways, and start to elucidate the molecular mechanisms that facilitate the switch between them.
Topics: Chaperone-Mediated Autophagy; Microautophagy; Autophagy; Endosomes; Lysosomes; Molecular Chaperones
PubMed: 38060380
DOI: 10.1016/j.celrep.2023.113529 -
FEBS Letters Oct 2023Ran-binding protein 2 (RANBP2)/Nup358 is a nucleoporin and a key component of the nuclear pore complex. Through its multiple functions (e.g., SUMOylation, regulation of... (Review)
Review
Ran-binding protein 2 (RANBP2)/Nup358 is a nucleoporin and a key component of the nuclear pore complex. Through its multiple functions (e.g., SUMOylation, regulation of nucleocytoplasmic transport) and subcellular localizations (e.g., at the nuclear envelope, kinetochores, annulate lamellae), it is involved in many cellular processes. RANBP2 dysregulation or mutation leads to the development of human pathologies, such as acute necrotizing encephalopathy 1, cancer, neurodegenerative diseases, and it is also involved in viral infections. The chromosomal region containing the RANBP2 gene is highly dynamic, with high structural variation and recombination events that led to the appearance of a gene family called RANBP2 and GCC2 Protein Domains (RGPD), with multiple gene loss/duplication events during ape evolution. Although RGPD homoplasy and maintenance during evolution suggest they might confer an advantage to their hosts, their functions are still unknown and understudied. In this review, we discuss the appearance and importance of RANBP2 in metazoans and its function-related pathologies, caused by an alteration of its expression levels (through promotor activity, post-transcriptional, or post-translational modifications), its localization, or genetic mutations.
Topics: Humans; Nuclear Pore Complex Proteins; Molecular Chaperones; Active Transport, Cell Nucleus; Nuclear Envelope
PubMed: 37795679
DOI: 10.1002/1873-3468.14749 -
MBio Oct 2023Dengue virus (DENV) is a major human pathogen that can cause hemorrhagic fever and shock syndrome. One important factor of DENV pathogenicity is non-structural protein 1...
Dengue virus (DENV) is a major human pathogen that can cause hemorrhagic fever and shock syndrome. One important factor of DENV pathogenicity is non-structural protein 1 (NS1), a glycoprotein that is secreted from infected cells. Here we study the mode of action of the widely used drug ivermectin, used to treat parasitic infections and recently shown to lower NS1 blood levels in DENV-infected patients. We found that ivermectin blocks the nuclear transport of transcription factors required for the expression of chaperones that support the folding and secretion of glycoproteins, including NS1. Impairing nuclear transport of these transcription factors by ivermectin or depleting them from infected cells dampens NS1 folding and thus its secretion. These results reveal a novel mode of action of ivermectin that might apply to other flaviviruses as well.
Topics: Humans; Dengue Virus; Dengue; Endoplasmic Reticulum Chaperone BiP; Ivermectin; Karyopherins; Molecular Chaperones; Transcription Factors; Viral Nonstructural Proteins
PubMed: 37702492
DOI: 10.1128/mbio.01441-23