Lysosomal Biology and Function: Modern View of Cellular Debris Bin
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Common Features of All Cells Bacterial
www.denniskunkel.com Tour of the Cell part 1 Today’s Topics • Finish Nucleic Acids Cells • Properties of all cells – Prokaryotes and Eukaryotes • Functions of Major Cellular Organelles – Information – Synthesis&Transport – Energy Conversion – Recycling – Structure and Movement Bacterial cell Animal Cell 9/12/12 (Prokaryote) (Eukaryote) 2 www.denniskunkel.com Common features of all cells • Plasma Membrane – defines inside from outside • Cytosol – Semifluid “inside” of the cell • DNA “chromosomes” - Genetic material – hereditary instructions • Ribosomes – “factories” to synthesize proteins 4 Plasma membrane Bacterial (Prokaryotic) Cell Ribosomes! Plasma membrane! Bacterial Cell wall! chromosome ! Phospholipid bilayer Proteins 0.5 !m! Flagella! No internal membranes 5 6 1 Figure 6.2b 1 cm Eukaryotic Cell Frog egg 1 mm Human egg 100 µm Most plant and animal cells 10 m µ Nucleus Most bacteria Light microscopy Mitochondrion 1 µm Super- 100 nm Smallest bacteria Viruses resolution microscopy Ribosomes 10 nm Electron microscopy Proteins Lipids 1 nm Small molecules Contains internal organelles 7 0.1 nm Atoms endoplasmicENDOPLASMIC RETICULUM reticulum (ER) ENDOPLASMIC RETICULUM (ER) NUCLEUS NUCLEUS Rough ER Smooth ER nucleus Rough ER Smooth ER Nucleus Plasma membrane Plasma membrane Centrosome Centrosome cytoskeletonCYTOSKELETON CYTOSKELETON Microfilaments You should Microfilaments Intermediate filaments know everything Intermediate filaments Microtubules in Fig 6.9 ribosomesRibosomes Microtubules Ribosomes cytosol GolgiGolgi apparatus apparatus Golgi apparatus Peroxisome Peroxisome In animal cells but not plant cells: In animal cells but not plant cells: Lysosome Lysosomes Lysosome Lysosomes Figure 6.9 Centrioles Figure 6.9 Centrioles Mitochondrion lysosome Flagella (in some plant 9sperm) Mitochondrion Flagella (in some plant10 sperm) mitochondrion Nuclear envelope Nucleus Nucleus 1 !m Nucleolus Chromatin Nuclear envelope: Inner membrane Outer membrane Pores Pore complex Rough ER Surface of nuclear envelope. -
Review: Microbial Transformations of Human Bile Acids Douglas V
Guzior and Quinn Microbiome (2021) 9:140 https://doi.org/10.1186/s40168-021-01101-1 REVIEW Open Access Review: microbial transformations of human bile acids Douglas V. Guzior1,2 and Robert A. Quinn2* Abstract Bile acids play key roles in gut metabolism, cell signaling, and microbiome composition. While the liver is responsible for the production of primary bile acids, microbes in the gut modify these compounds into myriad forms that greatly increase their diversity and biological function. Since the early 1960s, microbes have been known to transform human bile acids in four distinct ways: deconjugation of the amino acids glycine or taurine, and dehydroxylation, dehydrogenation, and epimerization of the cholesterol core. Alterations in the chemistry of these secondary bile acids have been linked to several diseases, such as cirrhosis, inflammatory bowel disease, and cancer. In addition to the previously known transformations, a recent study has shown that members of our gut microbiota are also able to conjugate amino acids to bile acids, representing a new set of “microbially conjugated bile acids.” This new finding greatly influences the diversity of bile acids in the mammalian gut, but the effects on host physiology and microbial dynamics are mostly unknown. This review focuses on recent discoveries investigating microbial mechanisms of human bile acids and explores the chemical diversity that may exist in bile acid structures in light of the new discovery of microbial conjugations. Keywords: Bile acid, Cholic acid, Conjugation, Microbiome, Metabolism, Microbiology, Gut health, Clostridium scindens, Enterocloster bolteae Introduction the development of healthy or diseased states. For The history of bile example, abnormally high levels of the microbially modi- Bile has been implicated in human health for millennia. -
Evidence for an Alternate Pathway for Lysosomal Enzyme Targeting (Oligosaccharides/Lysosomes/Phosphorylation) CHRISTOPHER A
Proc. NatL Acad. Sci. USA Vol. 80, pp. 775-779, February 1983 Cell Biology Identification and characterization of cells deficient in the mannose 6-phosphate receptor: Evidence for an alternate pathway for lysosomal enzyme targeting (oligosaccharides/lysosomes/phosphorylation) CHRISTOPHER A. GABEL, DANIEL E. GOLDBERG, AND STUART KORNFELD Departments of Internal Medicine and Biological Chemistry, Division of Hematology-Oncology, Washington University School of Medicine, St. Louis, Missouri 63110 Contributed by Stuart Kornfeld, November 3, 1982 ABSTRACT Newly synthesized lysosomal enzymes acquire dence that this cell line is deficient in Man-6-P receptor activity. phosphomannosyl units, which allow bindingofthe enzymes to the We also identify several additional cell lines that lack receptor mannose 6-phosphate receptor and subsequent translocation to activity yet possess high levels ofintracellular hydrolase activity. lysosomes. In some cell types, this sequence ofevents is necessary These data indicate that some cells possess pathways indepen- for the delivery ofthese enzymes to lysosomes. Using a slime mold dent of the Man-6-P receptor for the intracellular transport of lysosomal hydrolase as a probe, we have identified three murine acid hydrolases to lysosomes. cell lines that lack the receptor and one line that contains very low (3%) receptor activity. Each ofthese lines synthesizes the mannose MATERIALS AND METHODS 6-phosphate recognition marker on its lysosomal enzymes, but, Cells. BW5147 mouse lymphoma, P388D1 mouse macro- unlike cell lines with high levels of receptor, the cells accumulate MOPC 315 oligosaccharides containing phosphomonoesters. The receptor- phage, J774.2 mouse macrophage, mouse L cells, deficient lines possess high levels of intracellular acid hydrolase mouse myeloma, Chinese hamster ovary (CHO), and (human) activity, which is contained in dense granules characteristic of ly- HeLa cells were grown in suspension culture in a minimal es- sosomes. -
Ribonuclease A: Disulfide Bonds, Conformational Stability, and Cytotoxicity
Ribonuclease A: Disulfide Bonds, Conformational Stability, and Cytotoxicity by Tony A. Klink A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Biochemistry) at the UNIVERSITY OF WISCONSIN-MADISON 2()()() r OJ A dissertation entitled Ribonuclease A: Disulfide Bonds, Conformational Stability and Cytotoxicity submitted to the Graduate School of the University of Wisconsin-Madison in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Tony Anthony Klink Date of Final Oral Examination: August 4, 2000 Month & Year Degree to be awarded: December May August 2000 • * * * * * * • * * • * • • • • • * • • • * • • • • • • • • • • • • • * * • * • * * * • * • * • • • • • • * App oval Signature. f Dissertation Readers: Signature, Dean of Graduate School ---..., v.C~vJ,1A. 5. lJ,~k;at 1 Abstract Disulfide bonds between the side chains of cysteine residues are the only common cross links in proteins. Bovine pancreatic ribonuclease A (RNase A) is a 124-residue enzyme that contains four interweaving disulfide bonds (Cys26-Cys84, Cys40-Cys95, Cys58-CysllO, and Cys65-Cys72) and catalyzes the cleavage of RNA. The contribution of each disulfide bond to the confonnational stability and catalytic activity of RNase A was detennined using variants in which each cystine was replaced independently with a pair of alanine residues. Of the four disulfide bonds, the Cys40-Cys95 and Cys65-Cys72 cross-links are the least important to confonnational stability. Removing these disulfide bonds leads to RNase A variants that have Tm values below that of the wild-type enzyme but above physiological temperature. Unlike wild-type RNase A. G88R RNase A is toxic to cancer cells. To investigate the relationship between conformational stability and cytotoxicity, the C40AlC95A and C65A1C72A variants were made in the G88R background. -
Cystine–Glutamate Antiporter Xct Deficiency Suppresses Tumor Growth While Preserving Antitumor Immunity
Cystine–glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity Michael D. Arensmana, Xiaoran S. Yanga, Danielle M. Leahya, Lourdes Toral-Barzaa, Mary Mileskia, Edward C. Rosfjorda, Fang Wanga, Shibing Dengb, Jeremy S. Myersa, Robert T. Abrahamb, and Christina H. Enga,1 aOncology Research & Development, Pfizer, Pearl River, NY 10965; and bOncology Research & Development, Pfizer, San Diego, CA 92121 Edited by William G. Kaelin Jr., Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, and approved April 2, 2019 (received for review September 1, 2018) T cell-invigorating cancer immunotherapies have near-curative Thus, tumor cells may rely on xCT to fulfill the majority of their potential. However, their clinical benefit is currently limited, as cysteine and GSH needs by importing cystine. only a fraction of patients respond, suggesting that these regimens Inhibition of xCT has been investigated as a therapeutic may benefit from combination with tumor-targeting treatments. As strategy for cancer based on observations that elevated xCT ex- oncogenic progression is accompanied by alterations in metabolic pression on tumor cells correlates with poor prognosis (10–12) pathways, tumors often become heavily reliant on antioxidant and that inhibition of xCT in preclinical studies suppresses tumor machinery and may be susceptible to increases in oxidative stress. growth (10, 12–14). However, these studies relied heavily on the The cystine–glutamate antiporter xCT is frequently overexpressed in use of sulfasalazine, a clinical compound used for the treatment cancer and fuels the production of the antioxidant glutathione; thus, of rheumatoid arthritis, ulcerative colitis, and Crohn’s disease. -
The Endomembrane System and Proteins
Chapter 4 | Cell Structure 121 Endosymbiosis We have mentioned that both mitochondria and chloroplasts contain DNA and ribosomes. Have you wondered why? Strong evidence points to endosymbiosis as the explanation. Symbiosis is a relationship in which organisms from two separate species depend on each other for their survival. Endosymbiosis (endo- = “within”) is a mutually beneficial relationship in which one organism lives inside the other. Endosymbiotic relationships abound in nature. We have already mentioned that microbes that produce vitamin K live inside the human gut. This relationship is beneficial for us because we are unable to synthesize vitamin K. It is also beneficial for the microbes because they are protected from other organisms and from drying out, and they receive abundant food from the environment of the large intestine. Scientists have long noticed that bacteria, mitochondria, and chloroplasts are similar in size. We also know that bacteria have DNA and ribosomes, just like mitochondria and chloroplasts. Scientists believe that host cells and bacteria formed an endosymbiotic relationship when the host cells ingested both aerobic and autotrophic bacteria (cyanobacteria) but did not destroy them. Through many millions of years of evolution, these ingested bacteria became more specialized in their functions, with the aerobic bacteria becoming mitochondria and the autotrophic bacteria becoming chloroplasts. The Central Vacuole Previously, we mentioned vacuoles as essential components of plant cells. If you look at Figure 4.8b, you will see that plant cells each have a large central vacuole that occupies most of the cell's area. The central vacuole plays a key role in regulating the cell’s concentration of water in changing environmental conditions. -
A Mitochondria–Lysosome Transport Pathway
RESEARCH HIGHLIGHTS Controlling enteric nerve Interestingly, inhibition of integrin signalling The authors used point mutations to establish cell migration or ROCK activity rescued directed migration of that residue Met 44 of actin was essential for the MEFs and normalized the migration of ENCCs F-actin-severing function of Mical. Manipulation A functional gastrointestinal system is in organ cultures. Although the precise function of Mical levels is known to generate abnormal dependent on the enteric nervous system, of Phactr4 remains to be discovered, these data bristle cell processes in Drosophila. In the present which is formed during embryogenesis through demonstrate its role in regulating lamellipodial study, mutation of the Met 44 actin residue colonization of the gut by enteric neural crest actin dynamics through cofilin activity suppressed Mical overexpression phenotypes cells (ENCCs). Now, Niswander and colleagues controlled by integrin and PP1 signalling. CKR and phenocopied Mical loss-of-function effects identify the protein phosphatase 1 (PP1)- and in Drosophila. Together, these findings establish actin-binding protein Phactr4 as a regulator actin as a direct substrate of Mical and reveal of directional and collective ENCC migration a specific oxidation-dependent mechanism (Genes Dev. 26, 69–81; 2012). Actin gets the oxidation to regulate actin filament dynamics and cell Analysis of mouse embryos expressing treatment from Mical processes in vivo. AIZ a Phactr4 mutation known to abolish PP1 binding revealed reduced enteric neuronal Mical, an enzyme mediating redox reactions, numbers and defective organization at is known to promote actin remodelling embryonic day 18.5, and reduced ENCC in response to semaphorin signalling by A mitochondria–lysosome numbers in the gut at earlier stages (E12.5). -
Determination of Pk, Values of the Histidine Side
Protein Science (1997), 6:1937-1944. Cambridge University Press. Printed in the USA Copyright 0 1997 The Protein Society Determination of pK, values of the histidine side chains of phosphatidylinositol-specific phospholipase C from Bacillus cereus by NMR spectroscopy and site-directed mutagenesis TUN LIU, MARGRET RYAN, FREDERICK W. DAHLQUIST, AND 0. HAYES GRIFFITH Institute of Molecular Biology and Department of Chemistry, University of Oregon, Eugene, Oregon 97403 (RECEIVEDDecember 4, 1996: ACCEPTEDMay 19, 1997) Abstract Two active site histidine residues have been implicated in the catalysis of phosphatidylinositol-specific phospholipase C (PI-PLC). In this report, we present the first study of the pK,, values of histidines of a PI-PLC. All six histidines of Bacillus cereus PI-PLC were studied by 2D NMR spectroscopy and site-directed mutagenesis. The protein was selec- tively labeled with '3C"-histidine. A series of 'H-I3C HSQC NMR spectra were acquired over a pH range of 4.0-9.0. Five of the six histidines have been individually substituted with alanine to aid the resonance assignments in the NMR spectra. Overall, the remaining histidines in the mutants show little chemical shift changes in the 'H-"C HSQC spectra, indicating that the alanine substitution has no effect on the tertiary structure of the protein. H32A and H82A mutants are inactive enzymes, while H92A and H61A are fully active, and H81A retains about 15% of the wild-type activity. The active site histidines, His32 and His82, display pK,, values of 7.6 and 6.9, respectively. His92 and His227 exhibit pK, values of 5.4 and 6.9. -
Phosphatases and Differentiation of the Golgi Apparatus
J. Cell Sci. 4, 455-497 (1969) 455 Printed in Great Britain PHOSPHATASES AND DIFFERENTIATION OF THE GOLGI APPARATUS MARIANNE DAUWALDER, W. G. WHALEY AND JOYCE E. KEPHART The Cell Research Institute, Tlie University of Texas at Austin, Texas, U.S.A. SUMMARY Cytochemical techniques for the electron microscopic localization of inosine diphosphatase, thiamine pyrophosphatase, and acid phosphatase have been applied to the developing root tip of Zea mays. Following formaldehyde fixation the Golgi apparatus of most of the cells showed reaction specificity for IDPase and TPPase. Following glutaraldehyde fixation marked localiza- tion of IDPase reactivity in the Golgi apparatus was limited to the root cap, the epidermis, and the phloem. A parallelism was apparent between the sequential morphological development of the apparatus for the secretion of a polysaccharide product, the fairly direct incorporation of tritiated glucose into the apparatus to become a component of this product and the develop- ment of the enzyme reactivity. Acid phosphatase, generally accepted as a lysosomal marker, was found in association with the Golgi apparatus in only a few cell types near the apex of the root. The localization was usually in a single cisterna at the face of the apparatus toward which the production of secretory vesicles builds up and associated regions of what may be smooth endoplasmic reticulum. Since the cell types involved were limited regions of the cap and epidermis and some initial cells, no functional correlates of the reactivity were apparent. Despite the presence of this lysosomal marker, no structures clearly identifiable as ' lysosomes' were found and the lack of reaction specificity in the vacuoles did not allow them to be so defined. -
Endoplasmic Reticulum-Plasma Membrane Contact Sites Integrate Sterol and Phospholipid Regulation
RESEARCH ARTICLE Endoplasmic reticulum-plasma membrane contact sites integrate sterol and phospholipid regulation Evan Quon1☯, Yves Y. Sere2☯, Neha Chauhan2, Jesper Johansen1, David P. Sullivan2, Jeremy S. Dittman2, William J. Rice3, Robin B. Chan4, Gilbert Di Paolo4,5, Christopher T. Beh1,6*, Anant K. Menon2* 1 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada, 2 Department of Biochemistry, Weill Cornell Medical College, New York, New York, United States of a1111111111 America, 3 Simons Electron Microscopy Center at the New York Structural Biology Center, New York, New a1111111111 York, United States of America, 4 Department of Pathology and Cell Biology, Columbia University College of a1111111111 Physicians and Surgeons, New York, New York, United States of America, 5 Denali Therapeutics, South San a1111111111 Francisco, California, United States of America, 6 Centre for Cell Biology, Development, and Disease, Simon a1111111111 Fraser University, Burnaby, British Columbia, Canada ☯ These authors contributed equally to this work. * [email protected] (AKM); [email protected] (CTB) OPEN ACCESS Abstract Citation: Quon E, Sere YY, Chauhan N, Johansen J, Sullivan DP, Dittman JS, et al. (2018) Endoplasmic Tether proteins attach the endoplasmic reticulum (ER) to other cellular membranes, thereby reticulum-plasma membrane contact sites integrate sterol and phospholipid regulation. PLoS creating contact sites that are proposed to form platforms for regulating lipid homeostasis Biol 16(5): e2003864. https://doi.org/10.1371/ and facilitating non-vesicular lipid exchange. Sterols are synthesized in the ER and trans- journal.pbio.2003864 ported by non-vesicular mechanisms to the plasma membrane (PM), where they represent Academic Editor: Sandra Schmid, UT almost half of all PM lipids and contribute critically to the barrier function of the PM. -
A Genetic and Developmental Analysis of Dnase-1, an Acid Deoxyribonuclease in Droso~Hila Melano~Aster
A GENETIC AND DEVELOPMENTAL ANALYSIS OF DNASE-1, AN ACID DEOXYRIBONUCLEASE IN DROSOPHILA MEL~NOGASTER A Thesis Presented to the Faculty of the Graduate School in Partial Fulfillment for the Degree of Doctor of Philosophy by Charles Roger Detwiler Hay, 1979 BIOGRAPHICAL SKETCH Charles R. Detwiler was born on December 15, 1950 in Norristown, Pennsylvania. He attended Collegeville-Trappe High School in Trappe, Pennsylvania from 1964 to 1968; Houghton College in Houghton, New York from 1968 to 1972 (B.S., Zoology); Buc~~ell University in Lewisburg, Pennsylvania from 1972 to 1974 (M.S., Biology); and Cornell University in Ithaca, New York from 1974 to 1979 (Ph.D., 1979). At Cornell he was a National Institutes of Health Genetics Trainee. He is a member of the Genetics Society of America, the American Scientific Afffiliation, and of Phi Sigma, the National Honorary Biology Society. ii - To the Designer of the fly iii ACKNOWLEDGMENTS I would like to thank all my friends 1-rho by their moral support or careful critical attention contributed to the completion of this work. First, I would like to thank my major professor, Dr. Ross MacIntyre, for his patience, generosity, and valuable ideas. I would like to thank Dr. Richard Halberg and Dr. Bruce "\{allace for their helpful comments and criticisms 1-li th regard to the thesis project. I would like to thank Margaret Dean for tireless reassurances and valuable tecrillical assistance especially at the begLnning. Lastly, Beverly my wife is aCYil101-Iledged. It would be absurd to "thank" her. Her patience and devotion have served both in brlllging these pages together, and in keeping hw people together in one beautiful relationship. -
Transport of Sugars
BI84CH32-Frommer ARI 29 April 2015 12:34 Transport of Sugars Li-Qing Chen,1,∗ Lily S. Cheung,1,∗ Liang Feng,3 Widmar Tanner,2 and Wolf B. Frommer1 1Department of Plant Biology, Carnegie Institution for Science, Stanford, California 94305; email: [email protected] 2Zellbiologie und Pflanzenbiochemie, Universitat¨ Regensburg, 93040 Regensburg, Germany 3Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305 Annu. Rev. Biochem. 2015. 84:865–94 Keywords First published online as a Review in Advance on glucose, sucrose, carrier, GLUT, SGLT, SWEET March 5, 2015 The Annual Review of Biochemistry is online at Abstract biochem.annualreviews.org Soluble sugars serve five main purposes in multicellular organisms: as sources This article’s doi: of carbon skeletons, osmolytes, signals, and transient energy storage and as 10.1146/annurev-biochem-060614-033904 transport molecules. Most sugars are derived from photosynthetic organ- Copyright c 2015 by Annual Reviews. isms, particularly plants. In multicellular organisms, some cells specialize All rights reserved in providing sugars to other cells (e.g., intestinal and liver cells in animals, ∗ These authors contributed equally to this review. photosynthetic cells in plants), whereas others depend completely on an ex- Annu. Rev. Biochem. 2015.84:865-894. Downloaded from www.annualreviews.org ternal supply (e.g., brain cells, roots and seeds). This cellular exchange of Access provided by b-on: Universidade de Lisboa (UL) on 09/05/16. For personal use only. sugars requires transport proteins to mediate uptake or release from cells or subcellular compartments. Thus, not surprisingly, sugar transport is criti- cal for plants, animals, and humans.