[Reciprocal Between Autophagy And Inflammasome Activation]

by

ACKNOWLEDGEMENT

I would take this opportunity to thank my research supervisor, family and friends for their support and guidance without which this research would not have been possible.

DECLARATION

I, [type your full first names and surname here], declare that the contents of this dissertation/thesis represent my own unaided work, and that the dissertation/thesis has not previously been submitted for academic examination towards any qualification. Furthermore, it represents my own opinions and not necessarily those of the University.

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TABLE OF CONTENTS

ACKNOWLEDGEMENTII

DECLARATIONIII

CHAPTER 2: LITERATURE REVIEW5

1- Autophagy5

1-1 Autophagy Steps And The Molecular Machineray Of Autophagy7

1-2 Induction and Inhibition of Autophagy11

1-3 Autophagy And Resistance To Infection14

1-4 Selective Atophagy For The Invading Microbes18

1-5 How Immune Signalling Molecules Regulate Autophagy19

1-6 Role Of Autophagy In Innate Immunity22

1-7 Role of Autophagy In Acquired Immunity25

1-8 How Autophagy Protiens Regulate Immune Signalling28

1-9 Autophagy in Inflammatory Response31

1-10 Mechanisms By Which Autophagy Inhibit Inflammasome Activation35

1-11 Mechanisms By Which Inflammasome Inhibit Autophagy39

2- Pseudomonas Aeruginosa42

2-1 Pseudomonas Aeruginosa Infections44

2-2 Pseudomonas Aeruginosa Virulance Factors48

2-3 T3SS50

3- Inflammation52

4- TLR4 and its Signaling56

4-1 TLR4 as Sensor for Autophagy57

5-TRIF and INF-Beta Signaling pathway60

5-1 Role Of TLR4 And TRIF Signalling In Autophgy63

6-Inflammasome65

6-1 Caspase67

6-2 IL-1 Beta And Its Importance In Innate Immunity69

7-TNF Signaling Pathway71

8- Role Of Mitochondrial ROS In Inflammasome Activation During Autophagy73

9- Inflammasome Activation By Pseudomonas Aeruginosa79

10- Role of NLRC4 and Mitochondrial DNA in Activation of Inflammasome80

11- Intiation Of Inflammation Through Innate Pattern Recognition Receptors (PRRS)83

12-Relationship Between Autophagy And Apoptosis86

13-Role Of Inflammasome In Recognition Of Gram Negative Bacteria88

14- Autophagy an Emerging Immunological Paradigm89

15- Reciprocal Between Autophagy And Inflammasome Activation93

REFERENCES99

CHAPTER 2: LITERATURE REVIEW

1- Autophagy

Autophagy is an evolutionarily conserved process bywhich cytoplasmic proteins and organelles are catabolized1,2.During starvation, the protein TOR (target of rapamycin), a nutrient-responsive kinase, is inhibited, and this induces autophagy. In autophagy, doublemembrane autophagosomes envelop and sequester intracellular components and then fuse with lysosomes to form autolysosomes, which degrade their contents to regenerate nutrients. Current models of autophagy terminate with the degradation of the autophagosome cargo in autolysosomes3-5, but the regulation of autophagy in response to nutrients and the subsequent fate of the autolysosome are poorly understood. Here we show that mTOR signalling in rat kidney cells is inhibited during initiation of autophagy, but reactivated by prolonged starvation. Reactivation of mTOR is autophagy-dependent and requires the degradation of autolysosomal products. Increased mTOR activity attenuates autophagy and generates proto-lysosomal tubules and vesicles that extrude from autolysosomes and ultimately mature into functional lysosomes, thereby restoringthe full complement of lysosomes in the cell-a process we identify in multiple animal species. Thus, an evolutionarily conserved cycle in autophagy governs nutrient sensing and lysosome homeostasis during starvation.

Autophagy degrades cytoplasmic components that are required for cell survival in response to starvation1. Autophagy has also been associated with cell death, but it is unclear how this is distinguished from autophagy during cell survival. Drosophila salivary glands undergo programmed cell death that requires autophagy genes2, and engulfment of salivary gland cells by phagocytes does not appear to occur3. Here we show that Draper (Drpr), the Drosophila melanogaster orthologue of the Caenorhabditis elegans engulfment ...