proteasomes and its role in diseases

7/30/2019 proteasomes and its role in diseases

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PROTEASOME AND ITS

ROLE IN DISEASES

PRESENTER: DR. SUDHESNAMODERATOR: DR ALPANA SAXENA


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DISCOVERY 1977: Alfred Goldberg

2004: Aaron Ciechanover ,Avram Hershko ,Irwin Rose


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STRUCTURE: UPS

UBIQUITIN :tag that marks protein for degradation

8.5KD , 76 amino acids

Isopeptide bond :Carboxy terminal glycine residue ofUb with amino group of lysine residue on a protein

Requires ATP

3 enzymes: E1-Ub activating enzyme

E2-Ub conjugating enzyme

E3-Ub protein ligase


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Which proteins are ubiquitinated ?

Based on aminoterminal amino acid :

N-terminal rule

Cyclin destruction boxes

PEST sequence: proline glutamic acid , serine,threonine -signal peptide for degradation


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PROTEASOME 26S proteosome 20S catalytic unit

19S regulatory unit


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Active sites : 1) chymotrypsin like

2) trypsin like

3) peptidylglutamyl peptide hydrolyzing (PGPH)


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Processes regulated by protein

degradation

Gene transcription

Cell cycle progression

Circadian rhythms

Inflammatory response

Tumour suppression

Antigen processing


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Role in diseases


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Decreased proteasomal activity and

disease

Age related decrease in proteasome activity:

concentration of Ub-proteins

activity of the catalytic sites

Glycation and /or conjugation with lipid peroxidationproducts with the subunits

PA28 proteasome activator and 19S REG

Loss of Hsp 90 which protects 20S proteasome fromoxidative inactivation


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Cataract

capacity to remove oxidatively damaged proteins

26S proteasome is itself sensitive to oxidativeinactivation


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Neurodegenerative diseases

20S proteasome activity ( substantia nigra , striatum ,cerebral cortex, spinal cord)

Accumulation of abnormal proteins

Development of neurodegenerative diseases (PD, AD,HD, ALS)

Protein inclusions/misfolded oligomers furtherinhibit proteasome activity


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Parkinsons disease

Mutations in parkin gene

Parkin is a Ub-protein ligase

Parkin-associated endothelial like (Pael) receptor isoverexpressed in PD , parkin ubiquitinates it and promotes

its degradation

Mutations of ubiquitin carboxyterminal hydrolase (Decrease Ub recycling)

Proteasome inhibitor causes PD like syndrome

Knocking out PSMC1 gene that codes a subunit of 19Sproteasome causes Lewy body like inclusions.


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Enhanced proteasome activity in

diseases

Muscle atrophy (CKD , Type 1 DM , sepsis ,cachexia andstarvation) :

protein synthesis and protein degradation

Enhanced transcription of genes encoding proteasomesubunits

mRNA levels of 19S regulator subunit

Proteasome inhibitors like lactacystin , PSIprevented sepsis induced protein degradation

Role of NF


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Cancer

Both antiapoptotic and proapoptotic effects

Proteasomes degrade pro-apototic proteins Bax,Bid,p53,bcl-2 and cell cycle regulators pRb, cyclin D,p27

Proteasomes are involved in DNA damage signallingprocesses like IR-induced foci formation ofphosphorylated ATM , 53BPI,BS1, BRCA1, FANCD2,RAD 51

These pathways were inhibited by proteasomeinhibitors

Sensitization of tumor cells to chemotherapeuticagents


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Multiple myeloma

NFtranscription activator Causes proliferation of multiple myeloma cells

Increased levels of proteasome and mRNA (enzymaticimmunoassay and northern blot analysis )

Bortezomib :


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Multiple myeloma


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Role in immune system

Immunoproteasome :

Peptide Ag displayed by the MHC class 1on APC are products

of proteasomal degradation of proteins of pathogens.

specialized complex induced by IFN-.

Composed of1i, 2i, 5i and 11S regulatory particle

Cervical carcinoma and melanoma: defective 5i Cytotoxic

immune response suppression

HIV : suppression of synthesis of2i


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Acute GVHD:

Systemic protease inhibition by Bortezomib leadsto :

apoptosis of alloreactive T lymphocytes

inhibition of NF

Autoimmune disorders :

Proteosome inhibition inhibition of NF

decreases iNOS

In trials for Rheumatoid arthritis and Multiple

sclerosis


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Drugs: PS-341

Bortezomib (Velcade)

Salinosporin/Salinosporamide

Indications:

Multiple myeloma

Mantle cell lymphoma

Solid Organ transplantations

Rheumatoid arthritis

Multiple sclerosis


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Thank you

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proteasomes and its role in diseases