Secretory Lysosomes and Diseases

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1 ISSN CN / Q http / / cjbmb bjmu edu cn Chinese Journal of Biochemistry and Molecular Biology ~ * Rab27a ATP Rab27a Q25 Secretory Lysosomes and Diseases WANG Jun-Wei 1 ZHOU Yi-Jiang 2 1 ZHU Ke-Qing 3 * 1 Department of Neurobiology Zhejiang University School of Medicine Hangzhou 2 Zhejiang University School of Medicine Hangzhou China 3 Department of Pathology Zhejiang University School of Medicine Hangzhou China China Abstract The classical lysosomes contain a variety of hydrolytic enzymes and lipase to decompose proteins and membrane structures and considered as the cellular terminus digestive organelle The secretory lysosomes are dicovered in certain cell types with the functions of both intracellular digestion and regulatory exocytosis Rab27a plays a central role in the regulation of the exocytosis of lysosomal proteins The exocytosis-related gene mutations particularly in the regulatory proteins can cause a variety of immune deficiency phenotypes The ATP released from the astrocytes lysosomes can be used as the transmission signal between neurons and glial cells The secretory lysosomes also get involved in the invasion and metastasis of cancer cells Key words secretory lysosomes exocytosis Rab27a T B ph 3 40 T No Y T * Tel zhukeqing@ zju edu cn Received August Accepted November Supported by Natural Science Foundation of Zhejiang Province No Y * Corresponding author Tel zhukeqing@ zju edu cn

2 2 131 natural killer cell NK Rab1-Rab43 Rab3 Rab3A / B / C / D tumor necrosis factor TNF Rab27 Rab27A / B PC12 Rab3a Rab27a PC12 B 12 Rab27a Rab Rab27a 1 3 ATP Rab27a 13 4 Munc13-4 Munc13-4 JFC NK T Rab27a 3 Slp synaptotagminlike protein Slp / Rab cytotoxic T lymphocyte CTL Slac2 Slp C2 / Noc2 Munc Slp / Rab N C Rab27a Rab27a peripheral central supramolecular activation complex psmac F- 2 microtubule organizing centre 11 JFC1 Munc13-4 Rab27a Rab27a Slac2 MTOC Rab27a Va VIIa IL-1b ATP Slp Ca Rab27a Rab27a 6 Rab27a Va VIIa Munc SNARE 9 10 Fig 1 2 Rab27a ATP T ATP ATP 3 G Rab27a N- Nethylmaleimide-sensitive factor attachment protein Ca 2 + kiss and run 18 SNARE 18 ATP receptors SNARE ATP Rab- vesicular nucleotide transporter VNUT GTP 60

3 Fig 1 Secretory lysosome exocytosis A Stage 1 on recognition of a target cell by the natural killer NK cell a lytic immunological synapse forms at the point of contact with the target cell and the actin cytoskeleton is reorganized forming a ring of F-actin around the psmac B Stage 2 the MTOC and secretory lysosomes become polarized towards the lytic synapse It is likely that the secretory lysosomes move along microtubules to the lytic synapse but this has not been confirmed in NK cells C Stage 3 secretory lysosomes then move into close apposition with the plasma membrane a process known as docking D Stage 4 finally the secretory lysosomes fuse with the plasma membrane releasing their cytotoxic contents towards the target cell plasma membrane 11 CHS Griscelli GS Hermansky- Pudlak HPS CHS CHS 21 CHS Fig 2 23 LYST / CHS1 CHSI 24 GS T ATP ATP 19 Zhang 18 KCN potassium cyanide ATP ATP ATP Fig 2 CHS-16 fibroblasts have enlarged lysosomes P2X7 19 A LAMP-3 staining green in control fibroblasts shows ATP lysosomes distributed throughout the cell arrows B Enlarged view of LAMP-3 in control fibroblasts C LAMP-3 green in CHS-16 fibroblasts shows accumulation volume-activated anion channel VAACs of enlarged lysosomes in the perinuclear area arrows ATP D nlarged view of LAMP-3 in CHS-16 fibroblasts 20 showing some normal-sized lysosomes in the peripheral area arrowheads Co-staining with BODIPY 558 /568 4 phalloidin red visualizes the cell boundaries the DAPI stain blue visualizes the nucleus Scale bars 20 mm Chediak-Higashi 25

4 2 133 Rab27a Ashen Rab27a mrna mirna GS Hermansky-Pudlak - Rab27a Rab27a HPS 15 Rab27a 10 BLOC- Hermansky-Pudak Griscelli Rab27a T ATP AP mrna mirna References 29 1 Holt O J Gallo F Griffiths G M Regulating secretory lysosomes B 30 B Cell Biol Mullins C B biogenesis J Bioessays 32 B 4 Burgoyne R D Morgan A 33 L 34 Mambula - 70 heat shock protein 70 HSP 70 hmunc13-4 J HSP70 LAMP1 35 v- WASp- SRc B 36 mrna mirna 37 Exp Med Bryceson Y T Rudd E Zheng C et al epidermal growth factor receptor EGFR EGFR 38 J J Biochem Blott E J Griffiths G M Secretory lysosomes J Nat Rev Mol Bonifacino J S The molecular machinery for lysosome Physiol Rev Secretory granule exocytosis J 5 Agulhon C Petravicz J McMullen A B et al What is the role of astrocyte alcium in neurophysiology J Neuron Menager M M Ménasché G Romao M et al Secretory cytotoxic granule maturation and exocytosis require the effector protein Nat Immunol Krzewski K Chen X Orange J S et al Formation of a WIP- actin- and myosin IIA-containing multiprotein complex in activated NK cells and its alteration by KIR inhibitory signaling J J Cell Biol Andzelm M M Chen X Krzewski K et al Myosin IIA is required for cytolytic granule exocytosis in human NK cells J J Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 FHL4 patients J Blood

5 Marcet-Palacios M Odemuyiwa S O Coughlin J J et al Vesicleassociated membrane protein 7 VAMP-7 is essential for target cell killing in a natural killer cell line J Biochem Biophys Res Commun Topham N J Hewitt E W Natural killer cell cytotoxicity how do they pull the trigger J Immunology Tsuboi T Fukuda M Rab3A and Rab27A cooperatively regulate the docking step of dense-core vesicle exocytosis in PC12 cells J J Cell Sci pt Fukuda M Versatile role of Rab27 in membrane trafficking focus on the Rab27 effector families J J Biochem Tokyo Brzezinska A A Johnson J L Munafo D B The Rab27a effectors JFC1 / Slp1 and Munc13-4 regulate exocytosis of neutrophil granules J Traffic Munafó D B Johnson J L Ellis B A et al Rab27a is a key component of the secretory machinery of a zurophilic granules in granulocytes J Biochem J Tolmachova T Anders R Stinchcombe J et al A general role for Rab27a in secretory cells J Mol Biol Cell Hume AN Collinson LM Rapak A et al Rab27a regulates the peripheral distribution of melanosomes in melanocytes J J Cell Biol Zhang Z Chen G Zhou W et al Regulated ATP release from astrocytes through lysosome exocytosis J Nat Cell Biol Hayashi T Shoji M Abe K Molecular mechanisms of ischemic neuronal cell death -with relevance to Alzheimer s disease J Curr Alzheimer Res Duan S Neary J T P2X 7 receptors properties and relevance to CNS function J Glia Fields R D Ni Y Nonsynaptic communication through ATP release from volume-activated anion channels in axons J Sci Signal ra73 22 Westbroek W Adams D HuizingM et al Cellulardefects in Chediak-Higashi syndrome correlate with the molecular genotype and clinical phenotype J J Invest Dermatol Manoli I Golas G Westbroek W et al Chediak-Higashi syndrome with early developmental delay resulting from paternal heterodisomy of chromosome 1 J Am J Med Genet A A Kaplan J De Domenico I Ward D M Chediak-Higashi syndrome J Curr Opin Hematol Clark R Griffiths G M Lytic granules secretory lysosomes and disease J Curr Opin Immunol Gautam R Novak E K Tan J et al Interaction of Hermansky- Pudlak syndrome genes in the regulation of lysosome-related organelles J Traffic Clark R H Stinchcombe J C Day A et al Adaptor protein 3- dependent microtubule-mediated movement of lytic granules to the immunological synapse J Nat Immunol Fontana S Parolini S Vermi W et al Innate immunity defects in Hermansky-Pudlak type 2 syndrome J Blood Mohamed M M Sloane B F Cysteine cathepsins multifunctional enzymes in cancer J Nat Reviews Cancer Krueger S Haeckel C Buehling F et al A Inhibitory effects of antisense cathepsin B cdna transfection on invasion and motility in a human osteosarcoma cell line J Cancer Res Roshy S Sloane B F Moin K Pericellular cathepsin B and malignant progression J Cancer Metastasis Rev Yanamandra N Gumidyala KV Waldron KG et al Blockade of cathepsin B expression in human glioblastoma cells is associated with suppression of angiogenesis J Oncogene Szpaderska A M Silberman S Ahmed Y et al A Sp1 regulates cathepsin B transcription and invasiveness in murine B16 melanoma cells J Anticancer Res Roth W Deussing J Botchkarev VA et al Cathepsin L deficiency as molecular defect of furless hyperproliferation of keratinocytes and pertubation of hair follicle cycling J FASEB J Mambula S S Calderwood SK Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes J J Immunol Tu C Ortega-Cava C F Chen G et al Lysosomal cathepsin B participates in the podosome -mediated extracellular matrix degradation and invasion via secreted lysosomes in v-sc fibroblasts J Cancer Res Skog J Würdinger T van Rijn S et al Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers J Nat Cell Biol Al-Nedawi K Meehan B Micallef J et al Intercellular transfer of the oncogenic receptor EGFRvⅢ by microvesicles derived from tumour cells J Nat Cell Biol McCarthy N Biol Oncogenesis A sideways move J Nat Cell

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