bims-glucam 2021-12-05 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021–12–05
fiveteen papers selected by
Sreeparna Banerjee, Middle East Technical University

CircAKT3 promotes cell proliferation, survival and glutamine metabolism of gastric cancer by activating SLC1A5 expression via targeting miR-515-5p.
Amino acid deprivation induces AKT activation by inducing GCN2/ATF4/REDD1 axis.
Metabolic reprogramming by driver mutation-tumor microenvironment interplay in pancreatic cancer: new therapeutic targets.
Glutamine deprivation triggers NAGK-dependent hexosamine salvage.
Morin inhibits the transformation of fibroblasts towards myofibroblasts through regulating "PPAR-γ-glutaminolysis-DEPTOR" pathway in pulmonary fibrosis.
Elucidating tumor-stromal metabolic crosstalk in colorectal cancer through integration of constraint-based models and LC-MS metabolomics.
Blood Levels of Glutamine and Nitrotyrosine in Patients with Chronic Viral Hepatitis.
Cysteine is a limiting factor for glioma proliferation and survival.
Metabolic Reprogramming in the Tumor Microenvironment With Immunocytes and Immune Checkpoints.
Targeting cancer metabolism in the era of precision oncology.
SLC25A1 promotes tumor growth and survival by reprogramming energy metabolism in colorectal cancer.
Serine catabolism generates liver NADPH and supports hepatic lipogenesis.
Targeting the metabolism of cancer stem cells by energy disruptor molecules.
Starvation-induced proteasome assemblies in the nucleus link amino acid supply to apoptosis.
Bend or break: how biochemically versatile molecules enable metabolic division of labor in clonal microbial communities.

Histol Histopathol. 2021 Dec 01. 18401

CircAKT3 promotes cell proliferation, survival and glutamine metabolism of gastric cancer by activating SLC1A5 expression via targeting miR-515-5p.

Fei Li, Lixiao Zhang, Qi Sun.

BACKGROUND: Gastric cancer (GC) is a common disorder in the population. Numerous studies have reported that the pathogenesis of GC is implicated in the dysregulation of circular RNAs (circRNAs). The aim of this study was to investigate the role and functional mechanism of circ_0000199 (circAKT3) in GC.
METHODS: The expression of circAKT3, miR-515-5p and solute carrier family 1 member 5 (SLC1A5) mRNA was measured by quantitative real-time PCR (qPCR). Cell proliferation was assessed by cell counting kit-8 (CCK-8) assay, colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) assay. Cell apoptosis was determined by flow cytometry assay and caspase 3/7 activity. The protein levels of glutaminase (GLS), proliferating cell nuclear antigen (PCNA) and cleaved-caspase3 were detected by western blot. The binding relationship between miR-515-5p and circAKT3 or SLC1A5 was verified by dual-luciferase reporter assay or RIP assay. The role of circAKT3 in vivo was investigated by establishing animal models. The abundance of Ki-67 and PCNA was detected by IHC assay.
RESULTS: The expression of circAKT3 in GC tissues and cells was enhanced. The knockdown of circAKT3 inhibited GC cell proliferation, survival and glutamine metabolism, as well as tumor growth in animal models. MiR-515-5p was a target of circAKT3, and miR-515-5p suppressed the expression of SLC1A5 by binding to SLC1A5 3'UTR. CircAKT3 relieved the inhibition of miR-515-5p on SLC1A5 expression by targeting miR-515-5p. The effects of circAKT3 knockdown were reversed by miR-515-5p depletion, and the effects of miR-515-5p restoration were abolished by SLC1A5 overexpression.
CONCLUSION: CircAKT3 promotes the malignant development of GC by activating SLC1A5 expression via targeting miR-515-5p.

DOI: https://doi.org/10.14670/HH-18-401
Cell Death Dis. 2021 Dec 03. 12(12): 1127

Amino acid deprivation induces AKT activation by inducing GCN2/ATF4/REDD1 axis.

Hyeon-Ok Jin, Sung-Eun Hong, Ji-Young Kim, Se-Kyeong Jang, In-Chul Park.

Amino acid availability is sensed by various signaling molecules, including general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). However, it is unclear how these sensors are associated with cancer cell survival under low amino acid availability. In the present study, we investigated AKT activation in non-small cell lung cancer (NSCLC) cells deprived of each one of 20 amino acids. Among the 20 amino acids, deprivation of glutamine, arginine, methionine, and lysine induced AKT activation. AKT activation was induced by GCN2/ATF4/REDD1 axis-mediated mTORC2 activation under amino acid deprivation. In CRISPR-Cas9-mediated REDD1-knockout cells, AKT activation was not induced by amino acid deprivation, indicating that REDD1 plays a major role in AKT activation under amino acid deprivation. Knockout of REDD1 sensitized cells cultured under glutamine deprivation conditions to radiotherapy. Taken together, GCN2/ATF4/REDD1 axis induced by amino acid deprivation promotes cell survival signal, which might be a potential target for cancer therapy.

DOI: https://doi.org/10.1038/s41419-021-04417-w
Cancer Metastasis Rev. 2021 Dec 02.

Metabolic reprogramming by driver mutation-tumor microenvironment interplay in pancreatic cancer: new therapeutic targets.

Henriette Berg Andersen, Renata Ialchina, Stine Falsig Pedersen, Dominika Czaplinska.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers globally with a mortality rate exceeding 95% and very limited therapeutic options. A hallmark of PDAC is its acidic tumor microenvironment, further characterized by excessive fibrosis and depletion of oxygen and nutrients due to poor vascularity. The combination of PDAC driver mutations and adaptation to this hostile environment drives extensive metabolic reprogramming of the cancer cells toward non-canonical metabolic pathways and increases reliance on scavenging mechanisms such as autophagy and macropinocytosis. In addition, the cancer cells benefit from metabolic crosstalk with nonmalignant cells within the tumor microenvironment, including pancreatic stellate cells, fibroblasts, and endothelial and immune cells. Increasing evidence shows that this metabolic rewiring is closely related to chemo- and radioresistance and immunosuppression, causing extensive treatment failure. Indeed, stratification of human PDAC tumors into subtypes based on their metabolic profiles was shown to predict disease outcome. Accordingly, an increasing number of clinical trials target pro-tumorigenic metabolic pathways, either as stand-alone treatment or in conjunction with chemotherapy. In this review, we highlight key findings and potential future directions of pancreatic cancer metabolism research, specifically focusing on novel therapeutic opportunities.

Keywords:  Acidosis; Clinical trials; Glycolysis; Lipid metabolism; Metabolic subtypes; PDAC

DOI:  https://doi.org/10.1007/s10555-021-10004-4
Elife. 2021 11 30. pii: e62644. [Epub ahead of print]10

Glutamine deprivation triggers NAGK-dependent hexosamine salvage.

Sydney Campbell, Clementina Mesaros, Luke Izzo, Hayley Affronti, Michael Noji, Bethany E Schaffer, Tiffany Tsang, Kathryn Sun, Sophie Trefely, Salisa Kruijning, John Blenis, Ian A Blair, Kathryn E Wellen.

  Tumors frequently exhibit aberrant glycosylation, which can impact cancer progression and therapeutic responses. The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a major substrate for glycosylation in the cell. Prior studies have identified the HBP as a promising therapeutic target in pancreatic ductal adenocarcinoma (PDA). The HBP requires both glucose and glutamine for its initiation. The PDA tumor microenvironment is nutrient poor, however, prompting us to investigate how nutrient limitation impacts hexosamine synthesis. Here, we identify that glutamine limitation in PDA cells suppresses de novo hexosamine synthesis but results in increased free GlcNAc abundance. GlcNAc salvage via N-acetylglucosamine kinase (NAGK) is engaged to feed UDP-GlcNAc pools. NAGK expression is elevated in human PDA, and NAGK deletion from PDA cells impairs tumor growth in mice. Together, these data identify an important role for NAGK-dependent hexosamine salvage in supporting PDA tumor growth.

Keywords:  N-acetylglucosamine kinase; cancer biology; glutamine; hexosamine; human; mouse; pancreatic cancer

DOI:  https://doi.org/10.7554/eLife.62644
J Nutr Biochem. 2021 Nov 26. pii: S0955-2863(21)00343-0. [Epub ahead of print] 108923

Morin inhibits the transformation of fibroblasts towards myofibroblasts through regulating "PPAR-γ-glutaminolysis-DEPTOR" pathway in pulmonary fibrosis.

Yumeng Miao, Yanzhi Geng, Ling Yang, Yun Zheng, Yue Dai, Zhifeng Wei.

  Morin, a natural flavonoid exists in many foods and dietary plants, owns good bioactivities. Herein, we investigated its effect on pulmonary fibrosis (PF), and further explored the mechanisms. Results showed that morin remarkably improved the pathological alterations, and inhibited the transformation of fibroblasts towards myofibroblasts in lungs of mice with bleomycin-induced PF as well as TGF-β1 or hypoxia-stimulated NIH-3T3 cells. Mechanistic studies revealed that morin activated peroxisome proliferator activated receptor-gamma (PPAR-γ), and GW9662 or siPPAR-γ significantly weakened the inhibition of morin on the transformation of NIH-3T3 cells. Furthermore, morin restricted glutaminolysis by down-regulating the level of glutaminase 1 (GLS1), which was confirmed by glutamine deprivation and GLS1 overexpression. Replenishment of metabolite α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG) inhibited morin-prevented transformation of fibroblasts, but neither TGF-β1 nor hypoxia could induce the transformation of IDH2-knockdown fibroblasts, suggesting 2-HG was directly involved in the action of morin. Then, ubiquitination of DEPTOR was demonstrated to be prevented by morin, which was attributed to KDM4A, an enzyme inactivated by 2-HG, and leucine as well as KDM4A inhibitor obstructed the effect of morin. Finally, the mechanisms of morin were further confirmed in vivo. Collectively, morin inhibited PF through intervening in "PPAR-γ-glutaminolysis-DEPTOR" signals and subsequent restriction on the transformation of fibroblasts towards myofibroblasts.

Keywords:  PPAR-γ; glutaminolysis; morin; pulmonary fibrosis; transformation of fibroblasts towards myofibroblasts

DOI:  https://doi.org/10.1016/j.jnutbio.2021.108923
Metab Eng. 2021 Nov 25. pii: S1096-7176(21)00177-4. [Epub ahead of print]

Elucidating tumor-stromal metabolic crosstalk in colorectal cancer through integration of constraint-based models and LC-MS metabolomics.

Junmin Wang, Alireza Delfarah, Patrick Gelbach, Emma Fong, Paul Macklin, Shannon M Mumenthaler, Nicholas A Graham, Stacey Finley.

  Colorectal cancer (CRC) is a major cause of morbidity and mortality in the United States. Tumor-stromal metabolic crosstalk in the tumor microenvironment promotes CRC development and progression, but exactly how stromal cells, in particular cancer-associated fibroblasts (CAFs), affect the metabolism of tumor cells remains unknown. Here we take a data-driven approach to investigate the metabolic interactions between CRC cells and CAFs, integrating constraint-based modeling and metabolomic profiling. Using metabolomics data, we perform unsteady-state parsimonious flux balance analysis to infer flux distributions for central carbon metabolism in CRC cells treated with or without CAF-conditioned media. We find that CAFs reprogram CRC metabolism through stimulation of glycolysis, the oxidative arm of the pentose phosphate pathway (PPP), and glutaminolysis as well as inhibition of the tricarboxylic acid cycle. To identify potential therapeutic targets, we simulate enzyme knockouts and find that CAF-treated CRC cells are especially sensitive to inhibitions of hexokinase and glucose-6-phosphate, the rate limiting steps of glycolysis and oxidative PPP. Our work gives mechanistic insights into the metabolic interactions between CRC cells and CAFs and provides a framework for testing hypotheses towards CRC-targeted therapies.

Keywords:  Flux balance analysis; Mathematical biosciences; Metabolomics; Systems biology; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.ymben.2021.11.006
Int J Gen Med. 2021 ;14 8753-8762

Blood Levels of Glutamine and Nitrotyrosine in Patients with Chronic Viral Hepatitis.

Hussam Murad, Haythum Tayeb, Mahmoud Mosli, Misbahuddin Rafeeq, Mohammed Basheikh.

   Purpose: Oxidative stress is involved in pathogenesis of chronic viral hepatitis. Glutamine is an antioxidant, but there is a controversy about its risk-benefits. Nitrotyrosine is an oxidative stress marker. This observational cross-sectional study was designed to compare blood levels of glutamine and nitrotyrosine in treated versus untreated chronic viral hepatitis patients.
Patients and Methods: Five groups (n = 250) were included: hepatitis B untreated (HBV), hepatitis C untreated (HCV), HBV treated (HBVT), and HCV treated (HCVT) groups plus a normal control group. Liver function tests and blood levels of glutamine, nitrotyrosine, viral loads, and HBsAg were measured.
Results: Blood levels of glutamine and nitrotyrosine in all patient groups significantly increased compared with normal controls with non-significant differences in-between. Both tests showed significant large correlations with HBV-DNA or HCV-RNA test positivity, high accuracies, and cutoff scores with high sensitivities and specificities. The viral loads and HBsAg levels were significantly lower in treated versus untreated groups. However, they poorly correlated with levels of glutamine and nitrotyrosine in all patient groups.
Conclusion: Blood levels of glutamine and nitrotyrosine significantly increased in treated and untreated chronic viral hepatitis B and C patients compared with normal controls. Both tests showed high accuracies and cutoff scores with high sensitivities and specificities. However, they did not differ significantly in treated versus untreated patients. To our knowledge, this is the first data showing elevation of glutamine and nitrotyrosine in treated and untreated chronic viral hepatitis. A prospective longitudinal study with repeated measurements of glutamine and nitrotyrosine is recommended to verify if they can predict response to treatment. Study of other oxidative stress markers is also advised to clarify if the elevated nitrotyrosine could be an oxidative stress marker in these patients, and whether the increased glutamine could act as an antioxidant or as a predictive agent for deleterious consequences.

Keywords:  glutaminolysis; nitrotyrosination; oxidant stress

DOI:  https://doi.org/10.2147/IJGM.S337909
Mol Oncol. 2021 Dec 02.

Cysteine is a limiting factor for glioma proliferation and survival.

Victor Ruiz-Rodado, Tyrone Dowdy, Adrian Lita, Tamalee Kramp, Meili Zhang, Jinkyu Jung, Ana Dios-Esponera, Lumin Zhang, Christel C Herold-Mende, Kevin Camphausen, Mark R Gilbert, Mioara Larion.

  Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of the tumor dependence on external sources for some nutrients. However, little is known about the mechanisms that render cancer cells dependent on certain nutrients from the microenvironment. Herein, we report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. Using several 13 C-tracers and analysis of cystathionine synthase and cystathioninase levels, we revealed that glioma cells were not able to support GSH synthesis through the transsulfuration pathway, which allows methionine to be converted to cysteine in cysteine/cystine deprived conditions. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine-free diet survived longer, although this increase did not attain statistical significance, with concomitant reductions in plasma glutathione and cysteine levels. At the end point, however, tumors displayed the ability to synthesize glutathione, although higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine-related metabolites levels in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.

Keywords:  Glioma; cysteine; diet; glutathione; metabolism

DOI:  https://doi.org/10.1002/1878-0261.13148
Front Oncol. 2021 ;11 759015

Metabolic Reprogramming in the Tumor Microenvironment With Immunocytes and Immune Checkpoints.

Yaolin Xu, Lijie He, Qiang Fu, Junzhe Hu.

  Immune checkpoint inhibitors (ICIs), Ipilimumab, Nivolumab, Pembrolizumab and Atezolizumab, have been applied in anti-tumor therapy and demonstrated exciting performance compared to conventional treatments. However, the unsatisfactory response rates, high recurrence and adaptive resistance limit their benefits. Metabolic reprogramming appears to be one of the crucial barriers to immunotherapy. The deprivation of required nutrients and altered metabolites not only promote tumor progression but also confer dysfunction on immune cells in the tumor microenvironment (TME). Glycolysis plays a central role in metabolic reprogramming and immunoregulation in the TME, and many therapies targeting glycolysis have been developed, and their combinations with ICIs are in preclinical and clinical trials. Additional attention has been paid to the role of amino acids, lipids, nucleotides and mitochondrial biogenesis in metabolic reprogramming and clinical anti-tumor therapy. This review attempts to describe reprogramming metabolisms within tumor cells and immune cells, from the aspects of glycolysis, amino acid metabolism, lipid metabolism, nucleotide metabolism and mitochondrial biogenesis and their impact on immunity in the TME, as well as the significance of targeting metabolism in anti-tumor therapy, especially in combination with ICIs. In particular, we highlight the expression mechanism of programmed cell death (ligand) 1 [PD-(L)1] in tumor cells and immune cells under reprogramming metabolism, and discuss in detail the potential of targeting key metabolic pathways to break resistance and improve the efficacy of ICIs based on results from current preclinical and clinical trials. Besides, we draw out biomarkers of potential predictive value in ICIs treatment from a metabolic perspective.

Keywords:  PD-1; amino acid metabolism; glycolysis; immune checkpoints; lipid metabolism; mitochondrial biogenesis; nucleotide metabolism; the tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2021.759015
Nat Rev Drug Discov. 2021 Dec 03.

Targeting cancer metabolism in the era of precision oncology.

Zachary E Stine, Zachary T Schug, Joseph M Salvino, Chi V Dang.

One hundred years have passed since Warburg discovered alterations in cancer metabolism, more than 70 years since Sidney Farber introduced anti-folates that transformed the treatment of childhood leukaemia, and 20 years since metabolism was linked to oncogenes. However, progress in targeting cancer metabolism therapeutically in the past decade has been limited. Only a few metabolism-based drugs for cancer have been successfully developed, some of which are in - or en route to - clinical trials. Strategies for targeting the intrinsic metabolism of cancer cells often did not account for the metabolism of non-cancer stromal and immune cells, which have pivotal roles in tumour progression and maintenance. By considering immune cell metabolism and the clinical manifestations of inborn errors of metabolism, it may be possible to isolate undesirable off-tumour, on-target effects of metabolic drugs during their development. Hence, the conceptual framework for drug design must consider the metabolic vulnerabilities of non-cancer cells in the tumour immune microenvironment, as well as those of cancer cells. In this Review, we cover the recent developments, notable milestones and setbacks in targeting cancer metabolism, and discuss the way forward for the field.

DOI: https://doi.org/10.1038/s41573-021-00339-6
Cell Death Dis. 2021 Nov 27. 12(12): 1108

SLC25A1 promotes tumor growth and survival by reprogramming energy metabolism in colorectal cancer.

Ying Yang, Jiaxing He, Bo Zhang, Zhansheng Zhang, Guozhan Jia, Shiqi Liu, Tao Wu, Xianli He, Nan Wang.

Abnormal lipid metabolism has been commonly observed in various human cancers, including colorectal cancer (CRC). The mitochondrial citrate carrier SLC25A1 (also known as mitochondrial citrate/isocitrate carrier, CIC), has been shown to play an important role in lipid metabolism regulation. Our bioinformatics analysis indicated that SLC25A1 was markedly upregulated in CRC. However, the role of SLC25A1 in the pathogenesis and aberrant lipid metabolism in CRC remain unexplored. Here, we found that SLC25A1 expression was significantly increased in tumor samples of CRC as compared with paired normal samples, which is associated with poor survival in patients with CRC. Knockdown of SLC25A1 significantly inhibited the growth of CRC cells by suppressing the progression of the G1/S cell cycle and inducing cell apoptosis both in vitro and in vivo, whereas SLC25A1 overexpression suppressed the malignant phenotype. Additionally, we demonstrated that SLC25A1 reprogrammed energy metabolism to promote CRC progression through two mechanisms. Under normal conditions, SLC25A1 increased de novo lipid synthesis to promote CRC growth. During metabolic stress, SLC25A1 increased oxidative phosphorylation (OXPHOS) to protect protects CRC cells from energy stress-induced cell apoptosis. Collectively, SLC25A1 plays a pivotal role in the promotion of CRC growth and survival by reprogramming energy metabolism. It could be exploited as a novel diagnostic marker and therapeutic target in CRC.

DOI: https://doi.org/10.1038/s41419-021-04411-2
Nat Metab. 2021 Nov 29.

Serine catabolism generates liver NADPH and supports hepatic lipogenesis.

Zhaoyue Zhang, Tara TeSlaa, Xincheng Xu, Xianfeng Zeng, Lifeng Yang, Gang Xing, Gregory J Tesz, Michelle F Clasquin, Joshua D Rabinowitz.

Carbohydrate can be converted into fat by de novo lipogenesis, a process upregulated in fatty liver disease. Chemically, de novo lipogenesis involves polymerization and reduction of acetyl-CoA, using NADPH as the electron donor. The feedstocks used to generate acetyl-CoA and NADPH in lipogenic tissues remain, however, unclear. Here we show using stable isotope tracing in mice that de novo lipogenesis in adipose is supported by glucose and its catabolism via the pentose phosphate pathway to make NADPH. The liver, in contrast, derives acetyl-CoA for lipogenesis from acetate and lactate, and NADPH from folate-mediated serine catabolism. Such NADPH generation involves the cytosolic serine pathway in liver running in the opposite direction to that observed in most tissues and tumours, with NADPH made by the SHMT1-MTHFD1-ALDH1L1 reaction sequence. SHMT inhibition decreases hepatic lipogenesis. Thus, liver folate metabolism is distinctively wired to support cytosolic NADPH production and lipogenesis. More generally, while the same enzymes are involved in fat synthesis in liver and adipose, different substrates are used, opening the door to tissue-specific pharmacological interventions.

DOI: https://doi.org/10.1038/s42255-021-00487-4
Crit Rev Oncol Hematol. 2021 Nov 24. pii: S1040-8428(21)00332-2. [Epub ahead of print]169 103545

Targeting the metabolism of cancer stem cells by energy disruptor molecules.

Tahere Dadgar, Nasim Ebrahimi, Amir Reza Gholipour, Maryam Akbari, Leila Khani, Amirhossein Ahmadi, Michael R Hamblin.

  Cancer stem cells (CSCs) have been identified in various tumor types. CSCs are believed to contribute to tumor metastasis and resistance to conventional therapy. So targeting these cells could be an effective strategy to eliminate tumors and a promising new type of cancer treatment. Alterations in metabolism play an essential role in CSC biology and their resistance to treatment. The metabolic properties pathways in CSCs are different from normal cells, and to some extent, are different from regular tumor cells. Interestingly, CSCs can use other nutrients for their metabolism and growth. The different metabolism causes increased sensitivity of CSCs to agents that disrupt cellular homeostasis. Compounds that interfere with the central metabolic pathways are known as energy disruptors and can reduce CSC survival. This review highlights the differences between regular cancer cells and CSC metabolism and discusses the action mechanisms of energy disruptors at the cellular and molecular levels.

Keywords:  Cancer; Cancer stem cells; Energy disruptors; Metabolism

DOI:  https://doi.org/10.1016/j.critrevonc.2021.103545
Nat Commun. 2021 Nov 30. 12(1): 6984

Starvation-induced proteasome assemblies in the nucleus link amino acid supply to apoptosis.

Maxime Uriarte, Nadine Sen Nkwe, Roch Tremblay, Oumaima Ahmed, Clémence Messmer, Nazar Mashtalir, Haithem Barbour, Louis Masclef, Marion Voide, Claire Viallard, Salima Daou, Djaileb Abdelhadi, Daryl Ronato, Mohammadjavad Paydar, Anaïs Darracq, Karine Boulay, Nicolas Desjardins-Lecavalier, Przemyslaw Sapieha, Jean-Yves Masson, Mikhail Sergeev, Benjamin H Kwok, Laura Hulea, Frédérick A Mallette, Eric Milot, Bruno Larrivée, Hugo Wurtele, El Bachir Affar.

Eukaryotic cells have evolved highly orchestrated protein catabolic machineries responsible for the timely and selective disposal of proteins and organelles, thereby ensuring amino acid recycling. However, how protein degradation is coordinated with amino acid supply and protein synthesis has remained largely elusive. Here we show that the mammalian proteasome undergoes liquid-liquid phase separation in the nucleus upon amino acid deprivation. We termed these proteasome condensates SIPAN (Starvation-Induced Proteasome Assemblies in the Nucleus) and show that these are a common response of mammalian cells to amino acid deprivation. SIPAN undergo fusion events, rapidly exchange proteasome particles with the surrounding milieu and quickly dissolve following amino acid replenishment. We further show that: (i) SIPAN contain K48-conjugated ubiquitin, (ii) proteasome inhibition accelerates SIPAN formation, (iii) deubiquitinase inhibition prevents SIPAN resolution and (iv) RAD23B proteasome shuttling factor is required for SIPAN formation. Finally, SIPAN formation is associated with decreased cell survival and p53-mediated apoptosis, which might contribute to tissue fitness in diverse pathophysiological conditions.

DOI: https://doi.org/10.1038/s41467-021-27306-4
Genetics. 2021 Oct 02. pii: iyab109. [Epub ahead of print]219(2):

Bend or break: how biochemically versatile molecules enable metabolic division of labor in clonal microbial communities.

Sriram Varahan, Sunil Laxman.

  In fluctuating nutrient environments, isogenic microbial cells transition into "multicellular" communities composed of phenotypically heterogeneous cells, showing functional specialization. In fungi (such as budding yeast), phenotypic heterogeneity is often described in the context of cells switching between different morphotypes (e.g., yeast to hyphae/pseudohyphae or white/opaque transitions in Candida albicans). However, more fundamental forms of metabolic heterogeneity are seen in clonal Saccharomyces cerevisiae communities growing in nutrient-limited conditions. Cells within such communities exhibit contrasting, specialized metabolic states, and are arranged in distinct, spatially organized groups. In this study, we explain how such an organization can stem from self-organizing biochemical reactions that depend on special metabolites. These metabolites exhibit plasticity in function, wherein the same metabolites are metabolized and utilized for distinct purposes by different cells. This in turn allows cell groups to function as specialized, interdependent cross-feeding systems which support distinct metabolic processes. Exemplifying a system where cells exhibit either gluconeogenic or glycolytic states, we highlight how available metabolites can drive favored biochemical pathways to produce new, limiting resources. These new resources can themselves be consumed or utilized distinctly by cells in different metabolic states. This thereby enables cell groups to sustain contrasting, even apparently impossible metabolic states with stable transcriptional and metabolic signatures for a given environment, and divide labor in order to increase community fitness or survival. We speculate on possible evolutionary implications of such metabolic specialization and division of labor in isogenic microbial communities.

Keywords:  cross-feeding systems; division of labor; gluconeogenesis; glycolysis; metabolic specialization; phenotypic heterogeneity

DOI:  https://doi.org/10.1093/genetics/iyab109