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Fig. 4 | Arthritis Research & Therapy

Fig. 4

From: Systematic protein-protein interaction and pathway analyses in the idiopathic inflammatory myopathies

Fig. 4

Proposed ubiquitin proteasome pathway (UPP) involvement in idiopathic inflammatory myopathies (IIM). Endoplasmic reticulum (ER) stress leads to upregulation of the UPP. Ubiquitin binds to the E1 ubiquitin activating enzyme, which is then replaced by E2 ubiquitin conjugating enzyme. E3 ubiquitin ligase then brings in the target protein, in this example, inhibitor of nuclear factor kB (IkB), and catalyses repeated ligation to the ubiquitin. UBE3B is an E3 ligase. The polyubiquitinated protein is targeted to the 26S proteasome (of which PSMD3 is a component) and degraded. Peptide fragments can then be chaperoned by proteins such as HSPA1A/B to major histocompatibility complex (MHC) class I for presentation. The degradation of IkB results in activation of NFkB, which promotes production of MHC class I and inflammatory cytokines and inhibits MyoD. MHC class I overexpression results in further ER stress, MyoD inhibition results in reduced myoblast differentiation and inflammatory cytokines cause damage to muscle fibres

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