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Nature Communications Jan 2024The resilience of cellular proteostasis declines with age, which drives protein aggregation and compromises viability. The nucleus has emerged as a key quality control...
The resilience of cellular proteostasis declines with age, which drives protein aggregation and compromises viability. The nucleus has emerged as a key quality control compartment that handles misfolded proteins produced by the cytosolic protein biosynthesis system. Here, we find that age-associated metabolic cues target the yeast protein disaggregase Hsp104 to the nucleus to maintain a functional nuclear proteome during quiescence. The switch to respiratory metabolism and the accompanying decrease in translation rates direct cytosolic Hsp104 to the nucleus to interact with latent translation initiation factor eIF2 and to suppress protein aggregation. Hindering Hsp104 from entering the nucleus in quiescent cells results in delayed re-entry into the cell cycle due to compromised resumption of protein synthesis. In sum, we report that cytosolic-nuclear partitioning of the Hsp104 disaggregase is a critical mechanism to protect the latent protein synthesis machinery during quiescence in yeast, ensuring the rapid restart of translation once nutrients are replenished.
Topics: Cell Cycle; Cell Division; Cytosol; Protein Aggregates; Saccharomyces cerevisiae; Heat-Shock Proteins; Protein Biosynthesis; Saccharomyces cerevisiae Proteins
PubMed: 38182580
DOI: 10.1038/s41467-023-44538-8 -
Cells Feb 2022Unresolved hyperglycaemia, a hallmark of type 2 diabetes mellitus (T2DM), is a well characterised manifestation of altered fuel homeostasis and our understanding of its... (Review)
Review
Unresolved hyperglycaemia, a hallmark of type 2 diabetes mellitus (T2DM), is a well characterised manifestation of altered fuel homeostasis and our understanding of its role in the pathologic activation of the inflammatory system continues to grow. Metabolic disorders like T2DM trigger changes in the regulation of key cellular processes such as cell trafficking and proliferation, and manifest as chronic inflammatory disorders with severe long-term consequences. Activation of inflammatory pathways has recently emerged as a critical link between T2DM and inflammation. A substantial body of evidence has suggested that this is due in part to increased flux through the hexosamine biosynthetic pathway (HBP). The HBP, a unique nutrient-sensing metabolic pathway, produces the activated amino sugar UDP-GlcNAc which is a critical substrate for protein -GlcNAcylation, a dynamic, reversible post-translational glycosylation of serine and threonine residues in target proteins. Protein -GlcNAcylation impacts a range of cellular processes, including inflammation, metabolism, trafficking, and cytoskeletal organisation. As increased HBP flux culminates in increased protein -GlcNAcylation, we propose that targeting -GlcNAcylation may be a viable therapeutic strategy for the prevention and management of glucose-dependent pathologies with inflammatory components.
Topics: Diabetes Mellitus, Type 2; Glycosylation; Hexosamines; Humans; Inflammation; Protein Processing, Post-Translational; Proteins
PubMed: 35203353
DOI: 10.3390/cells11040705 -
Trends in Endocrinology and Metabolism:... Feb 2021β-Arrestin-1 and -2 are intracellular proteins that are able to inhibit signaling via G protein-coupled receptors (GPCRs). However, both proteins can also modulate... (Review)
Review
β-Arrestin-1 and -2 are intracellular proteins that are able to inhibit signaling via G protein-coupled receptors (GPCRs). However, both proteins can also modulate cellular functions in a G protein-independent fashion. During the past few years, studies with mutant mice selectivity lacking β-arrestin-1 and/or -2 in metabolically important cell types have led to novel insights into the mechanisms through which β-arrestins regulate key metabolic processes in vivo, including whole-body glucose and energy homeostasis. The novel information gained from these studies should inform the development of novel drugs, including β-arrestin- or G protein-biased GPCR ligands, that could prove useful for the therapy of several important pathophysiological conditions, including type 2 diabetes and obesity.
Topics: Animals; Humans; Mice; Protein Binding; Receptors, G-Protein-Coupled; Signal Transduction; beta-Arrestins
PubMed: 33358450
DOI: 10.1016/j.tem.2020.11.008 -
Biochemical Society Transactions Oct 2020Condensin and cohesin, both members of the structural maintenance of chromosome (SMC) family, contribute to the regulation and structure of chromatin. Recent work has... (Review)
Review
Condensin and cohesin, both members of the structural maintenance of chromosome (SMC) family, contribute to the regulation and structure of chromatin. Recent work has shown both condensin and cohesin extrude DNA loops and most likely work via a conserved mechanism. This review focuses on condensin complexes, highlighting recent in vitro work characterising DNA loop formation and protein structure. We discuss similarities between condensin and cohesin complexes to derive a possible mechanistic model, as well as discuss differences that exist between the different condensin isoforms found in higher eukaryotes.
Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Cell Cycle Proteins; Chaetomium; Chromosomal Proteins, Non-Histone; Chromosomes; Cryoelectron Microscopy; DNA; DNA-Binding Proteins; Dimerization; Gene Expression Regulation, Fungal; Humans; Multiprotein Complexes; Mutation; Nuclear Proteins; Protein Binding; Protein Conformation; Protein Domains; Protein Isoforms; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Cohesins
PubMed: 33005926
DOI: 10.1042/BST20200241 -
Biochimica Et Biophysica Acta.... Jun 2021Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two nuclear receptors that are well-known for their roles in xenobiotic detoxification by... (Review)
Review
Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two nuclear receptors that are well-known for their roles in xenobiotic detoxification by regulating the expression of drug-metabolizing enzymes and transporters. In addition to metabolizing drugs and other xenobiotics, the same enzymes and transporters are also responsible for the production and elimination of numerous endogenous chemicals, or endobiotics. Moreover, both PXR and CAR are highly expressed in the liver. As such, it is conceivable that PXR and CAR have major potentials to affect the pathophysiology of the liver by regulating the homeostasis of endobiotics. In recent years, the physiological functions of PXR and CAR in the liver have been extensively studied. Emerging evidence has suggested the roles of PXR and CAR in energy metabolism, bile acid homeostasis, cell proliferation, to name a few. This review summarizes the recent progress in our understanding of the roles of PXR and CAR in liver physiology.
Topics: Animals; Constitutive Androstane Receptor; Humans; Inactivation, Metabolic; Liver Diseases; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear; Xenobiotics
PubMed: 33600998
DOI: 10.1016/j.bbadis.2021.166101 -
International Journal of Molecular... Apr 2020Plants are able to synthesize all essential metabolites from minerals, water, and light to complete their life cycle. This plasticity comes at a high energy cost, and... (Review)
Review
Plants are able to synthesize all essential metabolites from minerals, water, and light to complete their life cycle. This plasticity comes at a high energy cost, and therefore, plants need to tightly allocate resources in order to control their economy. Being sessile, plants can only adapt to fluctuating environmental conditions, relying on quality control mechanisms. The remodeling of cellular components plays a crucial role, not only in response to stress, but also in normal plant development. Dynamic protein turnover is ensured through regulated protein synthesis and degradation processes. To effectively target a wide range of proteins for degradation, plants utilize two mechanistically-distinct, but largely complementary systems: the 26S proteasome and the autophagy. As both proteasomal- and autophagy-mediated protein degradation use ubiquitin as an essential signal of substrate recognition, they share ubiquitin conjugation machinery and downstream ubiquitin recognition modules. Recent progress has been made in understanding the cellular homeostasis of iron and sulfur metabolisms individually, and growing evidence indicates that complex crosstalk exists between iron and sulfur networks. In this review, we highlight the latest publications elucidating the role of selective protein degradation in the control of iron and sulfur metabolism during plant development, as well as environmental stresses.
Topics: Autophagy; Iron; Plant Proteins; Plants; Proteasome Endopeptidase Complex; Proteolysis; Sulfur; Ubiquitin
PubMed: 32316330
DOI: 10.3390/ijms21082771 -
The Journal of Clinical Investigation Nov 2021Growing tumors exist in metabolically compromised environments that require activation of multiple pathways to scavenge nutrients to support accelerated rates of growth....
Growing tumors exist in metabolically compromised environments that require activation of multiple pathways to scavenge nutrients to support accelerated rates of growth. The folliculin (FLCN) tumor suppressor complex (FLCN, FNIP1, FNIP2) is implicated in the regulation of energy homeostasis via 2 metabolic master kinases: AMPK and mTORC1. Loss-of-function mutations of the FLCN tumor suppressor complex have only been reported in renal tumors in patients with the rare Birt-Hogg-Dube syndrome. Here, we revealed that FLCN, FNIP1, and FNIP2 are downregulated in many human cancers, including poor-prognosis invasive basal-like breast carcinomas where AMPK and TFE3 targets are activated compared with the luminal, less aggressive subtypes. FLCN loss in luminal breast cancer promoted tumor growth through TFE3 activation and subsequent induction of several pathways, including autophagy, lysosomal biogenesis, aerobic glycolysis, and angiogenesis. Strikingly, induction of aerobic glycolysis and angiogenesis in FLCN-deficient cells was dictated by the activation of the PGC-1α/HIF-1α pathway, which we showed to be TFE3 dependent, directly linking TFE3 to Warburg metabolic reprogramming and angiogenesis. Conversely, FLCN overexpression in invasive basal-like breast cancer models attenuated TFE3 nuclear localization, TFE3-dependent transcriptional activity, and tumor growth. These findings support a general role of a deregulated FLCN/TFE3 tumor suppressor pathway in human cancers.
Topics: AMP-Activated Protein Kinases; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Neovascularization, Pathologic; Oxidative Phosphorylation; Proto-Oncogene Proteins; Tumor Suppressor Proteins; Warburg Effect, Oncologic
PubMed: 34779410
DOI: 10.1172/JCI144871 -
Experimental & Molecular Medicine May 2020Sterol regulatory element binding protein (SREBP) cleavage activating protein (SCAP) is a key regulator of SREBP maturation. SCAP induces translocation of SREBP from the... (Review)
Review
Sterol regulatory element binding protein (SREBP) cleavage activating protein (SCAP) is a key regulator of SREBP maturation. SCAP induces translocation of SREBP from the endoplasmic reticulum to the Golgi apparatus, allowing it to regulate cellular triglyceride and cholesterol levels. Previous studies have shown that suppression of SREBP activation in SCAP conditional knockout mice reduced the accumulation of intracellular triglycerides, which eventually causes the development of metabolic diseases such as atherosclerosis, diabetes, hepatic steatosis, and insulin resistance. However, despite the significance of SCAP as a regulator of SREBP, its function has not been thoroughly discussed. In this review, we have summarized the function of SCAP and its regulatory proteins. Furthermore, we discuss recent studies regarding SCAP as a possible therapeutic target for hypertriglyceridemia and hyperlipidemia.
Topics: Animals; Disease Susceptibility; Energy Metabolism; Humans; Intracellular Signaling Peptides and Proteins; Intracellular Space; Lipid Metabolism; Membrane Proteins; Metabolic Syndrome; Multiprotein Complexes; Protein Binding; Signal Transduction
PubMed: 32385422
DOI: 10.1038/s12276-020-0430-0 -
International Journal of Molecular... Nov 2021Most secreted and membrane proteins are targeted to and translocated across the endoplasmic reticulum (ER) membrane through the Sec61 protein-conducting channel.... (Review)
Review
Most secreted and membrane proteins are targeted to and translocated across the endoplasmic reticulum (ER) membrane through the Sec61 protein-conducting channel. Evolutionarily conserved Sec62 and Sec63 associate with the Sec61 channel, forming the Sec complex and mediating translocation of a subset of proteins. For the last three decades, it has been thought that ER protein targeting and translocation occur via two distinct pathways: signal recognition particle (SRP)-dependent co-translational or SRP-independent, Sec62/Sec63 dependent post-translational translocation pathway. However, recent studies have suggested that ER protein targeting and translocation through the Sec translocon are more intricate than previously thought. This review summarizes the current understanding of the molecular functions of Sec62/Sec63 in ER protein translocation.
Topics: Endoplasmic Reticulum; Heat-Shock Proteins; Membrane Transport Proteins; Protein Processing, Post-Translational; Protein Transport; SEC Translocation Channels; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 34884562
DOI: 10.3390/ijms222312757 -
Cells Dec 2020The biogenesis and function of eukaryotic cytochrome oxidase or mitochondrial respiratory chain complex IV (CIV) undergo several levels of regulation to adapt to... (Review)
Review
The biogenesis and function of eukaryotic cytochrome oxidase or mitochondrial respiratory chain complex IV (CIV) undergo several levels of regulation to adapt to changing environmental conditions. Adaptation to hypoxia and oxidative stress involves CIV subunit isoform switch, changes in phosphorylation status, and modulation of CIV assembly and enzymatic activity by interacting factors. The latter include the Hypoxia Inducible Gene Domain (HIGD) family yeast respiratory supercomplex factors 1 and 2 (Rcf1 and Rcf2) and two mammalian homologs of Rcf1, the proteins HIGD1A and HIGD2A. Whereas Rcf1 and Rcf2 are expressed constitutively, expression of HIGD1A and HIGD2A is induced under stress conditions, such as hypoxia and/or low glucose levels. In both systems, the HIGD proteins localize in the mitochondrial inner membrane and play a role in the biogenesis of CIV as a free unit or as part as respiratory supercomplexes. Notably, they remain bound to assembled CIV and, by modulating its activity, regulate cellular respiration. Here, we will describe the current knowledge regarding the specific and overlapping roles of the several HIGD proteins in physiological and stress conditions.
Topics: Animals; Cell Survival; Cytochromes c; Electron Transport Complex IV; Gene Expression Regulation, Enzymologic; Glucose; Humans; Hypoxia; Intracellular Signaling Peptides and Proteins; Mice; Mitochondrial Membranes; Mitochondrial Proteins; Oxidative Stress; Phosphorylation; Phylogeny; Protein Domains; Protein Isoforms; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 33291261
DOI: 10.3390/cells9122620