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Implications in Parkinson's Disease
Journal of Clinical Medicine Review Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease Silvia Paciotti 1,2 , Elisabetta Albi 3 , Lucilla Parnetti 1 and Tommaso Beccari 3,* 1 Laboratory of Clinical Neurochemistry, Department of Medicine, University of Perugia, Sant’Andrea delle Fratte, 06132 Perugia, Italy; [email protected] (S.P.); [email protected] (L.P.) 2 Section of Physiology and Biochemistry, Department of Experimental Medicine, University of Perugia, Sant’Andrea delle Fratte, 06132 Perugia, Italy 3 Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti, 06123 Perugia, Italy; [email protected] * Correspondence: [email protected] Received: 29 January 2020; Accepted: 20 February 2020; Published: 21 February 2020 Abstract: Ceramides are a family of bioactive lipids belonging to the class of sphingolipids. Sphingolipidoses are a group of inherited genetic diseases characterized by the unmetabolized sphingolipids and the consequent reduction of ceramide pool in lysosomes. Sphingolipidoses include several disorders as Sandhoff disease, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann Pick disease, Farber disease, and GM2 gangliosidosis. In sphingolipidosis, lysosomal lipid storage occurs in both the central nervous system and visceral tissues, and central nervous system pathology is a common hallmark for all of them. Parkinson’s disease, the most common neurodegenerative movement disorder, is characterized by the accumulation and aggregation of misfolded α-synuclein that seem associated to some lysosomal disorders, in particular Gaucher disease. This review provides evidence into the role of ceramide metabolism in the pathophysiology of lysosomes, highlighting the more recent findings on its involvement in Parkinson’s disease. Keywords: ceramide metabolism; Parkinson’s disease; α-synuclein; GBA; GLA; HEX A-B; GALC; ASAH1; SMPD1; ARSA * Correspondence [email protected] 1. -
Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Understanding the Molecular Pathobiology of Acid Ceramidase Deficiency
Understanding the Molecular Pathobiology of Acid Ceramidase Deficiency By Fabian Yu A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by Fabian PS Yu 2018 Understanding the Molecular Pathobiology of Acid Ceramidase Deficiency Fabian Yu Doctor of Philosophy Institute of Medical Science University of Toronto 2018 Abstract Farber disease (FD) is a devastating Lysosomal Storage Disorder (LSD) caused by mutations in ASAH1, resulting in acid ceramidase (ACDase) deficiency. ACDase deficiency manifests along a broad spectrum but in its classical form patients die during early childhood. Due to the scarcity of cases FD has largely been understudied. To circumvent this, our lab previously generated a mouse model that recapitulates FD. In some case reports, patients have shown signs of visceral involvement, retinopathy and respiratory distress that may lead to death. Beyond superficial descriptions in case reports, there have been no in-depth studies performed to address these conditions. To improve the understanding of FD and gain insights for evaluating future therapies, we performed comprehensive studies on the ACDase deficient mouse. In the visual system, we reported presence of progressive uveitis. Further tests revealed cellular infiltration, lipid buildup and extensive retinal pathology. Mice developed retinal dysplasia, impaired retinal response and decreased visual acuity. Within the pulmonary system, lung function tests revealed a decrease in lung compliance. Mice developed chronic lung injury that was contributed by cellular recruitment, and vascular leakage. Additionally, we report impairment to lipid homeostasis in the lungs. ii To understand the liver involvement in FD, we characterized the pathology and performed transcriptome analysis to identify gene and pathway changes. -
4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4). -
Genetic Ablation of Acid Ceramidase in Krabbe Disease Confirms the Psychosine Hypothesis and Identifies a New Therapeutic Target
Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target Yedda Lia, Yue Xub, Bruno A. Beniteza, Murtaza S. Nagreec, Joshua T. Dearborna, Xuntian Jianga, Miguel A. Guzmand, Josh C. Woloszynekb, Alex Giaramitab, Bryan K. Yipb, Joseph Elsberndb, Michael C. Babcockb, Melanie Lob, Stephen C. Fowlere, David F. Wozniakf, Carole A. Voglerd, Jeffrey A. Medinc,g, Brett E. Crawfordb, and Mark S. Sandsa,h,1 aDepartment of Medicine, Washington University School of Medicine, St. Louis, MO 63110; bDepartment of Research, BioMarin Pharmaceutical Inc., Novato, CA 94949; cDepartment of Medical Biophysics, University of Toronto, Toronto, ON M5S, Canada; dDepartment of Pathology, St. Louis University School of Medicine, St. Louis, MO 63104; eDepartment of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045; fDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110; gPediatrics and Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226; and hDepartment of Genetics, Washington University School of Medicine, St. Louis, MO 63110 Edited by William S. Sly, Saint Louis University School of Medicine, St. Louis, MO, and approved August 16, 2019 (received for review July 15, 2019) Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a generated catabolically through the deacylation of galactosylceramide fatal demyelinating disorder caused by a deficiency in the lyso- by acid ceramidase (ACDase). This effectively dissociates GALC somal enzyme galactosylceramidase (GALC). GALC deficiency leads deficiency from psychosine accumulation, allowing us to test the to the accumulation of the cytotoxic glycolipid, galactosylsphingosine long-standing psychosine hypothesis. We demonstrate that genetic (psychosine). Complementary evidence suggested that psychosine loss of ACDase activity [Farber disease (FD) (8)] in the twitcher is synthesized via an anabolic pathway. -
Phospholipase C-Related Catalytically Inactive Protein: a Novel Signaling Molecule for Modulating Fat Metabolism and Energy Expenditure
Journal of Oral Biosciences 61 (2019) 65e72 Contents lists available at ScienceDirect Journal of Oral Biosciences journal homepage: www.elsevier.com/locate/job Review Phospholipase C-related catalytically inactive protein: A novel signaling molecule for modulating fat metabolism and energy expenditure * Takashi Kanematsu a, b, , Kana Oue a, c, Toshiya Okumura a, Kae Harada a, 1, Yosuke Yamawaki a, 2, Satoshi Asano a, Akiko Mizokami d, Masahiro Irifune c, Masato Hirata e a Department of Cellular and Molecular Pharmacology, Division of Basic Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan b Department of Cell Biology and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka, 812-8582, Japan c Department of Dental Anesthesiology, Division of Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734- 8553, Japan d OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, 812-8582, Japan e Fukuoka Dental College, Fukuoka, 814-0193, Japan article info abstract Article history: Background: Overweight and obesity are defined as excessive or abnormal fat accumulation in adipose Received 16 March 2019 tissues, and increase the risk of morbidity in many diseases, including hypertension, dyslipidemia, type 2 Received in revised form diabetes, coronary heart disease, and stroke, through pathophysiological mechanisms. There is strong 17 April 2019 evidence that weight loss reduces the risk of metabolic syndrome by limiting blood pressure and Accepted 19 April 2019 improving the levels of serum triglycerides, total cholesterol, low-density lipoprotein-cholesterol, and Available online 15 May 2019 high-density lipoprotein-cholesterol. To date, several attempts have been made to develop effective anti- obesity medication or weight-loss drugs; however, satisfactory drugs for clinical use have not yet been Keywords: Adipose tissue developed. -
Expression Profiling of Ion Channel Genes Predicts Clinical Outcome in Breast Cancer
UCSF UC San Francisco Previously Published Works Title Expression profiling of ion channel genes predicts clinical outcome in breast cancer Permalink https://escholarship.org/uc/item/1zq9j4nw Journal Molecular Cancer, 12(1) ISSN 1476-4598 Authors Ko, Jae-Hong Ko, Eun A Gu, Wanjun et al. Publication Date 2013-09-22 DOI http://dx.doi.org/10.1186/1476-4598-12-106 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Ko et al. Molecular Cancer 2013, 12:106 http://www.molecular-cancer.com/content/12/1/106 RESEARCH Open Access Expression profiling of ion channel genes predicts clinical outcome in breast cancer Jae-Hong Ko1, Eun A Ko2, Wanjun Gu3, Inja Lim1, Hyoweon Bang1* and Tong Zhou4,5* Abstract Background: Ion channels play a critical role in a wide variety of biological processes, including the development of human cancer. However, the overall impact of ion channels on tumorigenicity in breast cancer remains controversial. Methods: We conduct microarray meta-analysis on 280 ion channel genes. We identify candidate ion channels that are implicated in breast cancer based on gene expression profiling. We test the relationship between the expression of ion channel genes and p53 mutation status, ER status, and histological tumor grade in the discovery cohort. A molecular signature consisting of ion channel genes (IC30) is identified by Spearman’s rank correlation test conducted between tumor grade and gene expression. A risk scoring system is developed based on IC30. We test the prognostic power of IC30 in the discovery and seven validation cohorts by both Cox proportional hazard regression and log-rank test. -
Supplementary Table S5. Differentially Expressed Gene Lists of PD-1High CD39+ CD8 Tils According to 4-1BB Expression Compared to PD-1+ CD39- CD8 Tils
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) J Immunother Cancer Supplementary Table S5. Differentially expressed gene lists of PD-1high CD39+ CD8 TILs according to 4-1BB expression compared to PD-1+ CD39- CD8 TILs Up- or down- regulated genes in Up- or down- regulated genes Up- or down- regulated genes only PD-1high CD39+ CD8 TILs only in 4-1BBneg PD-1high CD39+ in 4-1BBpos PD-1high CD39+ CD8 compared to PD-1+ CD39- CD8 CD8 TILs compared to PD-1+ TILs compared to PD-1+ CD39- TILs CD39- CD8 TILs CD8 TILs IL7R KLRG1 TNFSF4 ENTPD1 DHRS3 LEF1 ITGA5 MKI67 PZP KLF3 RYR2 SIK1B ANK3 LYST PPP1R3B ETV1 ADAM28 H2AC13 CCR7 GFOD1 RASGRP2 ITGAX MAST4 RAD51AP1 MYO1E CLCF1 NEBL S1PR5 VCL MPP7 MS4A6A PHLDB1 GFPT2 TNF RPL3 SPRY4 VCAM1 B4GALT5 TIPARP TNS3 PDCD1 POLQ AKAP5 IL6ST LY9 PLXND1 PLEKHA1 NEU1 DGKH SPRY2 PLEKHG3 IKZF4 MTX3 PARK7 ATP8B4 SYT11 PTGER4 SORL1 RAB11FIP5 BRCA1 MAP4K3 NCR1 CCR4 S1PR1 PDE8A IFIT2 EPHA4 ARHGEF12 PAICS PELI2 LAT2 GPRASP1 TTN RPLP0 IL4I1 AUTS2 RPS3 CDCA3 NHS LONRF2 CDC42EP3 SLCO3A1 RRM2 ADAMTSL4 INPP5F ARHGAP31 ESCO2 ADRB2 CSF1 WDHD1 GOLIM4 CDK5RAP1 CD69 GLUL HJURP SHC4 GNLY TTC9 HELLS DPP4 IL23A PITPNC1 TOX ARHGEF9 EXO1 SLC4A4 CKAP4 CARMIL3 NHSL2 DZIP3 GINS1 FUT8 UBASH3B CDCA5 PDE7B SOGA1 CDC45 NR3C2 TRIB1 KIF14 TRAF5 LIMS1 PPP1R2C TNFRSF9 KLRC2 POLA1 CD80 ATP10D CDCA8 SETD7 IER2 PATL2 CCDC141 CD84 HSPA6 CYB561 MPHOSPH9 CLSPN KLRC1 PTMS SCML4 ZBTB10 CCL3 CA5B PIP5K1B WNT9A CCNH GEM IL18RAP GGH SARDH B3GNT7 C13orf46 SBF2 IKZF3 ZMAT1 TCF7 NECTIN1 H3C7 FOS PAG1 HECA SLC4A10 SLC35G2 PER1 P2RY1 NFKBIA WDR76 PLAUR KDM1A H1-5 TSHZ2 FAM102B HMMR GPR132 CCRL2 PARP8 A2M ST8SIA1 NUF2 IL5RA RBPMS UBE2T USP53 EEF1A1 PLAC8 LGR6 TMEM123 NEK2 SNAP47 PTGIS SH2B3 P2RY8 S100PBP PLEKHA7 CLNK CRIM1 MGAT5 YBX3 TP53INP1 DTL CFH FEZ1 MYB FRMD4B TSPAN5 STIL ITGA2 GOLGA6L10 MYBL2 AHI1 CAND2 GZMB RBPJ PELI1 HSPA1B KCNK5 GOLGA6L9 TICRR TPRG1 UBE2C AURKA Leem G, et al. -
S1 Supplemental Materials Supplemental Methods Supplemental Figure 1. Immune Phenotype of Mcd19 Targeted CAR T and Dose Titratio
Supplemental Materials Supplemental Methods Supplemental Figure 1. Immune phenotype of mCD19 targeted CAR T and dose titration of in vivo efficacy. Supplemental Figure 2. Gene expression of fluorescent-protein tagged CAR T cells. Supplemental Figure 3. Fluorescent protein tagged CAR T cells function similarly to non-tagged counterparts. Supplemental Figure 4. Transduction efficiency and immune phenotype of mCD19 targeted CAR T cells for survival study (Figure 2D). Supplemental Figure 5. Transduction efficiency and immune phenotype of CAR T cells used in irradiated CAR T study (Fig. 3B-C). Supplemental Figure 6. Differential gene expression of CD4+ m19-humBBz CAR T cells. Supplemental Figure 7. CAR expression and CD4/CD8 subsets of human CD19 targeted CAR T cells for Figure 5E-G. Supplemental Figure 8. Transduction efficiency and immune phenotype of mCD19 targeted wild type (WT) and TRAF1-/- CAR T cells used for in vivo study (Figure 6D). Supplemental Figure 9. Mutated m19-musBBz CAR T cells have increased NF-κB signaling, improved cytokine production, anti-apoptosis, and in vivo function. Supplemental Figure 10. TRAF and CAR co-expression in human CD19-targeted CAR T cells. Supplemental Figure 11. TRAF2 over-expressed h19BBz CAR T cells show similar in vivo efficacy to h19BBz CAR T cells in an aggressive leukemia model. S1 Supplemental Table 1. Probesets increased in m19z and m1928z vs m19-musBBz CAR T cells. Supplemental Table 2. Probesets increased in m19-musBBz vs m19z and m1928z CAR T cells. Supplemental Table 3. Probesets differentially expressed in m19z vs m19-musBBz CAR T cells. Supplemental Table 4. Probesets differentially expressed in m1928z vs m19-musBBz CAR T cells. -
The Protein Phosphatase PP2A Plays Multiple Roles in Plant Development by Regulation of Vesicle Traffic—Facts and Questions
International Journal of Molecular Sciences Review The Protein Phosphatase PP2A Plays Multiple Roles in Plant Development by Regulation of Vesicle Traffic—Facts and Questions Csaba Máthé *, Márta M-Hamvas, Csongor Freytag and Tamás Garda Department of Botany, Faculty of Science and Technology, University of Debrecen, H-4032 Debrecen, Hungary; [email protected] (M.M.-H.); [email protected] (C.F.); [email protected] (T.G.) * Correspondence: [email protected] Abstract: The protein phosphatase PP2A is essential for the control of integrated eukaryotic cell functioning. Several cellular and developmental events, e.g., plant growth regulator (PGR) mediated signaling pathways are regulated by reversible phosphorylation of vesicle traffic proteins. Reviewing present knowledge on the relevant role of PP2A is timely. We discuss three aspects: (1) PP2A regulates microtubule-mediated vesicle delivery during cell plate assembly. PP2A dephosphorylates members of the microtubule associated protein family MAP65, promoting their binding to microtubules. Regulation of phosphatase activity leads to changes in microtubule organization, which affects vesicle traffic towards cell plate and vesicle fusion to build the new cell wall between dividing cells. (2) PP2A-mediated inhibition of target of rapamycin complex (TORC) dependent signaling pathways contributes to autophagy and this has possible connections to the brassinosteroid signaling pathway. (3) Transcytosis of vesicles transporting PIN auxin efflux carriers. PP2A regulates vesicle localization and recycling of PINs related to GNOM (a GTP–GDP exchange factor) mediated pathways. The proper intracellular traffic of PINs is essential for auxin distribution in the plant body, thus in whole Citation: Máthé, C.; M-Hamvas, M.; plant development. -
Studies on Cellular Nutrient Responses and Protein Degradation
STUDIES ON CELLULAR NUTRIENT RESPONSES AND PROTEIN DEGRADATION APPROVED BY SUPERVISORY COMMITTEE Melanie Cobb, Ph.D. (Mentor) Joel Goodman, Ph.D. (Chair) Paul Sternweis, Ph.D. Joseph Albanesi, Ph.D. DEDICATION: I dedicate this dissertation to my parents and grandparents, for inspiring me to pursue science, and for their unconditional love and support. STUDIES ON CELLULAR NUTRIENT RESPONSES AND PROTEIN DEGRADATION by ANWESHA GHOSH DISSERTATION / THESIS Presented to the Faculty of the Graduate School of Biomedical Sciences The University of Texas Southwestern Medical Center at Dallas In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY / MASTER OF SCIENCE / MASTER OF ARTS The University of Texas Southwestern Medical Center at Dallas Dallas, Texas August, 2015 Copyright by Anwesha Ghosh, 2015 All Rights Reserved iv STUDIES ON CELLULAR NUTRIENT RESPONSES AND PROTEIN DEGRADATION Publication No. Anwesha Ghosh The University of Texas Southwestern Medical Center at Dallas, Graduation Year Supervising Professor: Melanie H. Cobb (Ph.D.) I have worked on two projects. The first project investigates mechanisms involved in cellular responses to amino acids. Amino-acid abundance promotes protein synthesis and cell growth via activation of the protein kinase mTOR, while amino-acid deprivation promotes protein degradation by autophagy. The heterodimeric G protein coupled receptor (GPCR) T1R1-T1R3 can act as an extracellular sensor for amino acids, promoting mTOR activity while repressing autophagy in cells. Quantitative PCR analysis revealed that T1R3 depletion increases mRNA expression of amino acid transporters as a compensatory mechanism induced by perceived starvation. The arrestin proteins can bind GPCRs to mediate their internalization or to facilitate downstream signaling.