Two proteasome videos
Yesterday I watched two introductory videos on the ubiquitin-proteasome system - very important in autoimmunity, aging, cancer and neurodegeneration.
Alfred Goldberg, Functions of the proteasome, R&D Systems, recorded February 4, 2016:
Index:
9:30 start of presentation13:20 ubiquitin-proteasome pathway summary slide - ATP required 15:22 antigen presentation - 1% of product peptides are taken up by ER and displayed in cell surface by MHC class I molecules - proteasome allows immune system to screen intracellular space for abnormal proteins (pathogen or cancer) 23:16 multiple ATP dependent steps in proteasome function 38:00 Bortezmib - proteasome inhibitor, inhibits NF-kB, does not cross BBB, induces apoptosis 40:33 Endoplasmic-reticulum-associated protein degradation (ERAD) pathway is unusually activated in multiple myeloma cells ; proteasome inhibition results in increased ER stress and triggers UPR, further UPR activation triggers apoptosis 42:30 proteasome inhibitors are not more toxic since they mainly block chymotrypsin-like site & only partially inhibit protein degradation ; since myeloma cells have to break down lots of immunoglobins they become more stressed than other cells as a result 43:27 cells can compensate for proteasome inhibition thru Nrf1 activation (more proteasome) and increase in autophagy / lysosomal degradation 44:35 cAMP phosphorylation of 26S proteasome enhances degradation of misfolded proteins 45:50 cAMP dependent regulation of protein phosphorylation ; rolipram is PDE4 inhibitor 47:39 cAMP activation for treatment of neurodegenerative diseases 49:06 rolipram for taupathology ; rolipram increased proteasome activity and reduced tau accumulation in mouse model 50:36 summary slide - endogenous regulation (ubiquitination, DUBs) ; exogenous activation - phosphorylation of proteasome 52:13 Q&A
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- Does increased proteasome activity increase susceptibility to autoimmune diseases?
Female mice (FVBN) were found to have overall higher rates of proteasome activity than males and females are more susceptible to autoimmunity. However, proteasome activity differences are tissue specific.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132179/
"Further analysis of the chymotrypsin‐like activity between males and females revealed that, with the exception of the kidney, females show higher activity than males in the spinal cord and intestine (Fig 1E) and also higher trypsin‐like activity in spleen, kidney, and intestine (Fig 1F). Therefore, the mapping of the proteasome activity across multiple tissues and sexes suggests that females show an overall higher proteostasis capacity."
I have eczema and use Eucrisa, topical crisaborole, which is a PDE4 inhibitor. Eucrisa is also used to treat psoriasis, an autoimmune condition, so apparently PDE4 inhibition in skin does not exacerbate autoimmunity.
Verbrugge et al. (2015) Proteasome inhibitors as experimental therapeutics of autoimmune diseases - https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-015-0529-1
"The prominent role of the UPS [ubiquitin-proteasome system] in multiple cellular processes, including MHC-mediated antigen presentation, cytokine and cell cycle regulation and apoptosis, renders it crucial in the development and progression of inflammatory and autoimmune diseases [5]. Given that cytokines are regulatory factors in the formation of immunoproteasomes, it is conceivable that their increased levels would coincide with chronic inflammation. Indeed, elevated immunoproteasome levels have been associated with inflammation and the development and progression of autoimmunity [11,12]. However, it is still a controversial issue whether or not immunoproteasomes drive inflammatory diseases or merely reflect the consequence of excessive cytokine synthesis or cell stress."
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Video #2
Raymond Deshaies, A primer on the ubiquitin-proteasome system, iBiology, uploaded May 23, 2017
Index:
3:08 rapid turnover is important to dynamic regulation of the proteome 5:18 ~5% of genes are involved in ubiquitin modifications 11:43 ubiquitin glycine residue forms amide linkage with amino group of side chain of lysine residue on target protein 12:22 ubiquitin has 7 lysines and an amino terminus to which other ubiquitins can attach - 8 types of ubiquitin chain linkages, each has distinct biology 26:03 pseudosubstrate inhibitor - no lysine 28:53 oxygen sensing / hypoxia response ; prolyl hydroxylase uses molecular oxygen to hydroxylate a proline on HIF; the hydroxylated proline acts as a direct ligand for VHL ubiquitin ligase, HIF is ubiquitinated and destroyed by 26S proteasome 30:38 prolyl hydroxylase has lousy Km 31:20 VHL is a tumor suppressor protein ; loss of VHL increases cancer, esp. kidney cancer
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