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1. Introduction
2. The ER: a multifunctional organelle
3. Overview of the lecture
4. Outline
5. Implications
6. A few words of introduction
7. Our cells as seen by an artist
8. The plasma cell: a professional secretor of Ab
9. ER: rough in plasma cells
10. Rough ER
11. Plasma cells produce Ab - a multimeric molecule
12. Quality control in the protein factory
13. ER quality control
14. How do cells recognise misfoldedness
15. Thiol-mediated retension (1)
16. Thiol-mediated retension (2)
17. IgM pentamers and hexamers
18. The importance of retention
19. Retention in the ER
20. Terminal B lymphocyte differentiation
21. B cell and plasma cell differentiation
22. Biogenesis and developmental control of IgM
23. Generating oxidative conditions in the ER
24. ER oxidase 1, Ero1
25. Structure of Ero1
26. Electron transfer
27. Electron transfer in mammals
28. The Ero1 alpha/beta and the yeast homolog
29. Ero1 alpha/beta promote oxidative folding
30. Why there are two Ero1?
31. Adjusting oxidative power to the needs
32. Reduced PDI is needed for protein folding and QC
33. Controling Ero1 activity: preventing ER oxidation
34. Protein disulfide isomerase
35. PDI
36. Oxidoreductases in ER in mammalian cells
37. Why so many?
38. To allow competing reactions to coexist (oxi-red)
39. Surgical redox regulation in the ER
40. Many oxidoreductases in the ER
41. Oxidoreductases in the ER often tissue specific
42. How do cells prevent ER hyper-oxidation?
43. Cytosolic GSH roles in cargo proteins
44. Cytosolic GSH roles in mammalian cells
45. Most PDI is oxidized in the absence of cytosol
46. Cytosolic proteins and GSH
47. Cells respond to ER hyperoxidation
48. GSH level in response to Ero1 alpha expression
49. Cells adjust changes in the ER redox
50. Preventing excessive ER oxidation (1)
51. Mammalian Ero1s lack retention motifs
52. Ero1 localization depends on PDI or ERp44
53. Preventing excessive ER oxidation (2)
54. Ero1 alpha as a redox sensor
55. Active and inactive Ero1
56. Preventing excessive ER oxidation (3)
57. Phisiology of the Ero1-PDI interaction
58. ERp44 form mixed disulfides with Ero1 alpha
59. ERp44 structure
60. ERp44 interacts with IP3R type I
61. ERp44 mediates thiol-dependent retention
62. B lymphocytes and plasma cells polymerization
63. Is ERp44 important in IgM polymerization?
64. ERp44 and IgM levels while B cells differentiate
65. A platform for IgM polymerization?
66. ERp44 co-localised only in part with PDI
67. The ER as a two-step column
68. The effect of Ero1 localization in mammals
69. Ero1 alpha/beta level during B cell differentiation (1)
70. Ero1 alpha/beta level during B cell differentiation (2)
71. Reconverting an Ab factory
72. Plasma cell death
73. Ab production controled by plasma cells lifespan
74. A timer? a counter?
75. Death by exhaustion?
76. In vitro model of B to plasma cell differentiation
77. Apoptosis follows the IgM synthesis increase
78. IgM synthesis causes apoptosis via UPR pathway
79. Apoptosis decreases Chop
80. Signals emanating from the ER protein factory?
81. IgM quality control and ERAD
82. Death signals linked to protein degradation?
83. Proteasomes level in parallel to cargo production
84. Proteasome level during plasma cells differentiation
85. Functional consequences?
86. Accumulation of Poly-Ub proteins
87. Poly-Ub proteins and proteasome substrates
88. Slower proteasomal degradation
89. Mechanisms of apoptosis?
90. Role of Bcl-2 family proteins
91. Load exceeds capacity: death by self-pollUbtion?
92. Proteasome inhibitors as treatment of myeloma
93. Proteasomal impairment limits plasma lifespan
94. Problems in the factory: ER disease
95. Homeostasis in healthy ER / storage diseases
96. Congenital goiter
97. Russell bodies induced upon Ig-mu synthesis
98. Cellular indigestions
99. Concluding remarks
100. Thank you
101. References
102. References
103. 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

Links

Series:

• The Endoplasmic Reticulum

Categories:

• Cell Biology
• Immunology

Therapeutic Areas:

• Immunology & Inflammation

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 November 21, 2024, from https://doi.org/10.69645/JTJO8379.
Export Citation (RIS)

Publication History

• Published on October 1, 2007
• Archived on February 25, 2021

Financial Disclosures

• Prof. Roberto Sitia has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.