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Printable Handouts
Navigable Slide Index
- Introduction
- The ER: a multifunctional organelle
- Overview of the lecture
- Outline
- Implications
- A few words of introduction
- Our cells as seen by an artist
- The plasma cell: a professional secretor of Ab
- ER: rough in plasma cells
- Rough ER
- Plasma cells produce Ab - a multimeric molecule
- Quality control in the protein factory
- ER quality control
- How do cells recognise misfoldedness
- Thiol-mediated retension (1)
- Thiol-mediated retension (2)
- IgM pentamers and hexamers
- The importance of retention
- Retention in the ER
- Terminal B lymphocyte differentiation
- B cell and plasma cell differentiation
- Biogenesis and developmental control of IgM
- Generating oxidative conditions in the ER
- ER oxidase 1, Ero1
- Structure of Ero1
- Electron transfer
- Electron transfer in mammals
- The Ero1 alpha/beta and the yeast homolog
- Ero1 alpha/beta promote oxidative folding
- Why there are two Ero1?
- Adjusting oxidative power to the needs
- Reduced PDI is needed for protein folding and QC
- Controling Ero1 activity: preventing ER oxidation
- Protein disulfide isomerase
- PDI
- Oxidoreductases in ER in mammalian cells
- Why so many?
- To allow competing reactions to coexist (oxi-red)
- Surgical redox regulation in the ER
- Many oxidoreductases in the ER
- Oxidoreductases in the ER often tissue specific
- How do cells prevent ER hyper-oxidation?
- Cytosolic GSH roles in cargo proteins
- Cytosolic GSH roles in mammalian cells
- Most PDI is oxidized in the absence of cytosol
- Cytosolic proteins and GSH
- Cells respond to ER hyperoxidation
- GSH level in response to Ero1 alpha expression
- Cells adjust changes in the ER redox
- Preventing excessive ER oxidation (1)
- Mammalian Ero1s lack retention motifs
- Ero1 localization depends on PDI or ERp44
- Preventing excessive ER oxidation (2)
- Ero1 alpha as a redox sensor
- Active and inactive Ero1
- Preventing excessive ER oxidation (3)
- Phisiology of the Ero1-PDI interaction
- ERp44 form mixed disulfides with Ero1 alpha
- ERp44 structure
- ERp44 interacts with IP3R type I
- ERp44 mediates thiol-dependent retention
- B lymphocytes and plasma cells polymerization
- Is ERp44 important in IgM polymerization?
- ERp44 and IgM levels while B cells differentiate
- A platform for IgM polymerization?
- ERp44 co-localised only in part with PDI
- The ER as a two-step column
- The effect of Ero1 localization in mammals
- Ero1 alpha/beta level during B cell differentiation (1)
- Ero1 alpha/beta level during B cell differentiation (2)
- Reconverting an Ab factory
- Plasma cell death
- Ab production controled by plasma cells lifespan
- A timer? a counter?
- Death by exhaustion?
- In vitro model of B to plasma cell differentiation
- Apoptosis follows the IgM synthesis increase
- IgM synthesis causes apoptosis via UPR pathway
- Apoptosis decreases Chop
- Signals emanating from the ER protein factory?
- IgM quality control and ERAD
- Death signals linked to protein degradation?
- Proteasomes level in parallel to cargo production
- Proteasome level during plasma cells differentiation
- Functional consequences?
- Accumulation of Poly-Ub proteins
- Poly-Ub proteins and proteasome substrates
- Slower proteasomal degradation
- Mechanisms of apoptosis?
- Role of Bcl-2 family proteins
- Load exceeds capacity: death by self-pollUbtion?
- Proteasome inhibitors as treatment of myeloma
- Proteasomal impairment limits plasma lifespan
- Problems in the factory: ER disease
- Homeostasis in healthy ER / storage diseases
- Congenital goiter
- Russell bodies induced upon Ig-mu synthesis
- Cellular indigestions
- Concluding remarks
- Thank you
- References
- References
- References
Topics Covered
- Studies on the synthesis, assembly and secretion of antibodies during B cell development reveal fundamental properties of the endoplasmic reticulum as a protein factory
- How do cells regulate the formation, isomerisation and reduction of disulfide bonds?
- How do plasma cells manage to secrete massive amounts of antibodies?
- Is antibody production somehow controling plasma cell lifespan?
- Answers to these questions have profound implications in biotechnology and medicine, as they may help design better bioreactors for the production of recombinant proteins and better therapies for multiple myeloma and other secretory tumors
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Talk Citation
Sitia, R. (2007, October 1). The endoplasmic reticulum as a most efficient antibody factory [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 1, 2024, from https://doi.org/10.69645/JTJO8379.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Roberto Sitia has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.