PROTEASOME AND ITS ROLE IN DISEASES

PRESENTER: DR. SUDHESNA MODERATOR: DR ALPANA SAXENA

DISCOVERY
1977: Alfred Goldberg 2004: Aaron Ciechanover ,Avram Hershko ,Irwin Rose

STRUCTURE: UPS
UBIQUITIN :tag that marks protein for degradation 8.5KD , 76 amino acids Isopeptide bond :Carboxy terminal glycine residue of Ub 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

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

PROTEASOME
26S proteosome 20S catalytic unit 19S regulatory unit

 Active sites : 1) chymotrypsin like 2) trypsin like 3) peptidyl glutamyl peptide hydrolyzing (PGPH)

Processes regulated by protein degradation

Gene transcription Cell cycle progression Circadian rhythms Inflammatory response Tumour suppression Antigen processing

Role in diseases

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 peroxidation products with the subunits PA28 proteasome activator and 19S REG Loss of Hsp 90 which protects 20S proteasome from oxidative inactivation

Cataract
capacity to remove oxidatively damaged proteins
26S proteasome is itself sensitive to oxidative inactivation

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 further inhibit proteasome activity

Parkinsons disease
Mutations in parkin gene Parkin is a Ub-protein ligase Parkin-associated endothelial like (Pael) receptor is overexpressed 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 19S proteasome causes Lewy body like inclusions.

Enhanced proteasome activity in diseases

Muscle atrophy (CKD , Type 1 DM , sepsis ,cachexia and
starvation) : protein synthesis and protein degradation Enhanced transcription of genes encoding proteasome subunits mRNA levels of 19S regulator subunit

Proteasome inhibitors like lactacystin , PSI prevented sepsis induced protein degradation Role of NF

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 signalling processes like IR-induced foci formation of phosphorylated ATM , 53BPI,BS1, BRCA1, FANCD2, RAD 51 These pathways were inhibited by proteasome inhibitors Sensitization of tumor cells to chemotherapeutic agents

Multiple myeloma
NF transcription activator Causes proliferation of multiple myeloma cells Increased levels of proteasome and mRNA (enzymatic immunoassay and northern blot analysis ) Bortezomib :

Multiple myeloma

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 of 1i, 2i, 5i and 11S regulatory particle
Cervical carcinoma and melanoma: defective 5i Cytotoxic immune response suppression HIV : suppression of synthesis of 2i

Acute GVHD: Systemic protease inhibition by Bortezomib leads to : 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

Drugs: PS-341 Bortezomib (Velcade) Salinosporin/Salinosporamide Indications: Multiple myeloma Mantle cell lymphoma Solid Organ transplantations Rheumatoid arthritis Multiple sclerosis

Thank you