AUTOPHAGY

PRESENTED BY: Aditya Kanwal M.Tech Biotech 2012BT09

INTRODUCTION:
- It is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. - It disposes off organelles, proteins and even small intracellular pathogens that are too big to be processed by the proteasome complex. -The autophagy machinery also interfaces with most cellular stress response pathways , including those involved in controlling immune responses and inflammation.
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FORMATION OF AUTOPHAGOSOME:
The Various Steps involved are:
Sequestration --> Degradation --> Amino acid/peptide generation.

Autophagy : overview of the process

ROLE OF AUTOPHAGY IN IMMUNOLOGY:

- Relationship between Autophagy and components of Immune system is very complex. - The autophagy proteins function in both the induction and suppression of immune and inflammatory responses, and immune and inflammatory signals function in both the induction and suppression of autophagy.

-Plays various roles in immunology as mentioned below:

DEGRADATION OF INTRACELLULAR PATHOGENS:

- In addition to endogenous substrates, it also degrades intracellular pathogens in a selective form, called xenophagy. - Identification by LC3, p62, polyubiquitinilation, etc.

RESISTANCE TO INFECTION:
- The autophagy pathway and/or autophagy proteins have a crucial role in resistance to bacterial, viral and protozoan infection in organisms. - Mutations in autophagy related genes (coding for 31 Atg proteins) has been seen to increase the incidence and intensity of viral, fungal and bacterial infection in various organisms like Drosophila and mice. - In Humans, mutations in IRGM (Immunity related GTPase) has been related to an increased incidence of Tuberculosis and mutations in NOD2 has been related to increased incidence of Leprosy.

ROLES IN ADAPTIVE IMMUNITY:

- Functions in adaptive immunity, including in the development and homoeostasis of the immune system and in antigen presentation. - Knock-out of different autophagy genes in mice has shown to effect the populations of B1 cells, CD4 T cells, CD8 T cells and fetal haematopoietic stem cells
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- Also involved in the delivery of self-antigens to MHC class II loading compartments in epithelial cells of thymus. Genetic disruption of Atg5 in thymic epithelial cells leads to the altered selection of certain MHC class II restricted T-cell specificities and autoimmunity.

- Autophagy proteins may participate in different facets of antigen presentation like:

1) Delivery of endogenous antigens for MHC class II presentation to CD4+ T cells

2) The enhancement of antigen donor cell cross-presentation to CD8+ T cells,

REGULATION OF IMMUNE SIGNALLING:

- Autophagy proteins function in both the activation and inactivation of innate immune signalling.

- The autophagy pathway activates IFN production in dendritic cells by delivering viral nucleic acids to endosomal TLRs.

- They can also negatively regulate RIG-I-like receptor (RLR)mediated induction of IFN production through the autophagic elimination of damaged mitochondria and reduction of ROS.

IN INFLAMMATORY & AUTOIMMUNE DISEASES:

- May contribute to chronic inflammatory diseases and autoimmune diseases. - A link has been observed between mutations in autophagy regulators and Crohns disease, in which a breakdown in clearance or recognition of bacteria, as well as altered mucosal barrier function and cytokine production, is thought to lead to intestinal inflammation. - Three Crohns disease susceptibility genes have been identified i.e. IRGM, NOD2 and ATG16L1. - Emerging links include the autoimmune disease systemic lupus erythematosus (SLE), inflammation-associated metabolic diseases such as obesity and diabetes, and inflammation associated with cystic fibrosis lung disease.

REFERENCES:
1) Mizushima N, Autophagy : Process and Function.Genes Dev. 2007 21: 2861-2873. 2) Levine B, Mizushima N and Virgin H.W, Autophagy in immunity and inflammation. Nature. 2011 January 20; 469(7330): 323335.

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