Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Clinical Immunology
Published in: Journal of Clinical Immunology 1/2016

01-05-2016

Metabolic Control of Plasma Cell Differentiation- What We Know and What We Don't Know

Authors: Michael Aronov, Boaz Tirosh

Published in: Journal of Clinical Immunology | Special Issue 1/2016

Login to get access

Abstract

Antibody secretion is executed by plasma cells that are generated in the periphery and migrate to the bone marrow to establish a long lived pool. The terminal differentiation of B lymphocytes into plasma cells is executed by a network of transcription factors that cross-regulate each other in order to irreversibly promote this transition. While major progress has been made in the understanding the transcriptional activity of the underlying master regulators, much less is known on the metabolic regulation of plasma cell differentiation that is required to support antibody synthesis, folding and secretion at high levels and allow their long-lasting survival. In this review we will address the known cross talks between the transcription and metabolic control of plasma cells and elaborate on the gaps of knowledge in the field.
Literature
1.
Mancini R, Fagioli C, Fra AM, Maggioni C, Sitia R Degradation of unassembled soluble Ig subunits by cytosolic proteasomes: evidence that retrotranslocation and degradation are coupled events. FASEB Journal: official publication of the Federation of American Societies for Experimental Biology. 2000;14:769–78.
2.
Rabinovich E, Bar-Nun S, Amitay R, Shachar I, Gur B, Taya M, Haimovich J Different assembly species of IgM are directed to distinct degradation sites along the secretory pathway. J Biol Chem. 1993;268:24145–8.PubMed
3.
Anelli T, Ceppi S, Bergamelli L, Cortini M, Masciarelli S, Valetti C, Sitia R Sequential steps and checkpoints in the early exocytic compartment during secretory IgM biogenesis. EMBO J. 2007;26:4177–88.CrossRefPubMedPubMedCentral
4.
Martincic K, Alkan SA, Cheatle A, Borghesi L, Milcarek C Transcription elongation factor ELL2 directs immunoglobulin secretion in plasma cells by stimulating altered RNA processing. Nat Immunol. 2009;10:1102–9.CrossRefPubMedPubMedCentral
5.
Nutt SL, Taubenheim N, Hasbold J, Corcoran LM, Hodgkin PD The genetic network controlling plasma cell differentiation. Semin Immunol. 2011;23:341–9.CrossRefPubMed
6.
Willis SN, Good-Jacobson KL, Curtis J, Light A, Tellier J, Shi W, Smyth GK, Tarlinton DM, Belz GT, Corcoran LM, Kallies A, Nutt SL Transcription factor IRF4 regulates germinal center cell formation through a B cell-intrinsic mechanism. J Immunol. 2014;192:3200–6.CrossRefPubMed
7.
Klein U, Casola S, Cattoretti G, Shen Q, Lia M, Mo T, Ludwig T, Rajewsky K, Dalla-Favera R Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat Immunol. 2006;7:773–82.CrossRefPubMed
8.
Ochiai K, Maienschein-Cline M, Simonetti G, Chen J, Rosenthal R, Brink R, Chong AS, Klein U, Dinner AR, Singh H, Sciammas R Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4. Immunity. 2013;38:918–29.CrossRefPubMedPubMedCentral
9.
Turner Jr CA, Mack DH, Davis MM Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell. 1994;77:297–306.
10.
Ochiai K, Muto A, Tanaka H, Takahashi S, Igarashi K Regulation of the plasma cell transcription factor Blimp-1 gene by Bach2 and Bcl6. Int Immunol. 2008;20:453–60.CrossRefPubMed
11.
Muto A, Ochiai K, Kimura Y, Itoh-Nakadai A, Calame KL, Ikebe D, Tashiro S, Igarashi K Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch. EMBO J. 2010;29:4048–61.CrossRefPubMedPubMedCentral
12.
Alinikula J, Nera KP, Junttila S, Lassila O Alternate pathways for Bcl6-mediated regulation of B cell to plasma cell differentiation. Eur J Immunol. 2011;41:2404–13.CrossRefPubMed
13.
14.
15.
Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol. 2009;186:323–31.CrossRefPubMedPubMedCentral
16.
R. Sriburi, H. Bommiasamy, G.L. Buldak, G.R. Robbins, M. Frank, S. Jackowski, J.W. Brewer, Coordinate regulation of phospholipid biosynthesis and secretory pathway gene expression in XBP-1(S)-induced endoplasmic reticulum biogenesis, J Biol Chem, 282 (2007) 7024–7034.
17.
Lee AH, Chu GC, Iwakoshi NN, Glimcher LH XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J. 2005;24:4368–80.CrossRefPubMedPubMedCentral
18.
Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, Lee AH, Qian SB, Zhao H, Yu X, Yang L, Tan BK, Rosenwald A, Hurt EM, Petroulakis E, Sonenberg N, Yewdell JW, Calame K, Glimcher LH, Staudt LM XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity. 2004;21:81–93.CrossRefPubMed
19.
Novoa I, Zeng H, Harding HP, Ron D Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol. 2001;153:1011–22.CrossRefPubMedPubMedCentral
20.
Liu Z, Lv Y, Zhao N, Guan G, Wang J Protein kinase R-like ER kinase and its role in endoplasmic reticulum stress-decided cell fate. Cell Death Disease. 2015;6:e1822.CrossRefPubMedPubMedCentral
21.
Haze K, Yoshida H, Yanagi H, Yura T, Mori K Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell. 1999;10:3787–99.CrossRefPubMedPubMedCentral
22.
Lee K, Tirasophon W, Shen X, Michalak M, Prywes R, Okada T, Yoshida H, Mori K, Kaufman RJ IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev. 2002;16:452–66.CrossRefPubMedPubMedCentral
23.
Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM, Friend D, Grusby MJ, Alt F, Glimcher LH Plasma cell differentiation requires the transcription factor XBP-1. Nature. 2001;412:300–7.CrossRefPubMed
24.
Hu CC, Dougan SK, McGehee AM, Love JC, Ploegh HL XBP-1 regulates signal transduction, transcription factors and bone marrow colonization in B cells. EMBO J. 2009;28:1624–36.CrossRefPubMedPubMedCentral
25.
Taubenheim N, Tarlinton DM, Crawford S, Corcoran LM, Hodgkin PD, Nutt SL High rate of antibody secretion is not integral to plasma cell differentiation as revealed by XBP-1 deficiency. J Immunol. 2012;189:3328–38.CrossRefPubMed
26.
Ma Y, Shimizu Y, Mann MJ, Jin Y, Hendershot LM Plasma cell differentiation initiates a limited ER stress response by specifically suppressing the PERK-dependent branch of the unfolded protein response. Cell Stress Chaperones. 2010;15:281–93.CrossRefPubMedPubMedCentral
27.
Goldfinger M, Shmuel M, Benhamron S, Tirosh B Protein synthesis in plasma cells is regulated by crosstalk between endoplasmic reticulum stress and mTOR signaling. Eur J Immunol. 2011;41:491–502.CrossRefPubMed
28.
So JS, Hur KY, Tarrio M, Ruda V, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Lichtman AH, Iwawaki T, Glimcher LH, Lee AH Silencing of lipid metabolism genes through IRE1alpha-mediated mRNA decay lowers plasma lipids in mice. Cell Metab. 2012;16:487–99.CrossRefPubMedPubMedCentral
29.
Benhamron S, Hadar R, Iwawaky T, So JS, Lee AH, Tirosh B Regulated IRE1-dependent decay participates in curtailing immunoglobulin secretion from plasma cells. Eur J Immunol. 2014;44:867–76.CrossRefPubMed
30.
Bertolotti M, Sitia R, Rubartelli A On the redox control of B lymphocyte differentiation and function. Antioxid Redox Signal. 2012;16:1139–49.CrossRefPubMed
31.
Bertolotti M, Yim SH, Garcia-Manteiga JM, Masciarelli S, Kim YJ, Kang MH, Iuchi Y, Fujii J, Vene R, Rubartelli A, Rhee SG, Sitia R B- to plasma-cell terminal differentiation entails oxidative stress and profound reshaping of the antioxidant responses. Antioxid Redox Signal. 2010;13:1133–44.CrossRefPubMed
32.
Vincenz L, Jager R, O’Dwyer M, Samali A Endoplasmic reticulum stress and the unfolded protein response: targeting the Achilles heel of multiple myeloma. Mol Cancer Ther. 2013;12:831–43.CrossRefPubMed
33.
Gambella M, Rocci A, Passera R, Gay F, Omede P, Crippa C, Corradini P, Romano A, Rossi D, Ladetto M, Boccadoro M, Palumbo A High XBP1 expression is a marker of better outcome in multiple myeloma patients treated with bortezomib. Haematologica. 2014;99:e14–6.CrossRefPubMedPubMedCentral
34.
Raninga PV, Di Trapani G, Vuckovic S, Bhatia M, Tonissen KF Inhibition of thioredoxin 1 leads to apoptosis in drug-resistant multiple myeloma. Oncotarget. 2015;6:15410–24.CrossRefPubMedPubMedCentral
35.
van Anken E, Romijn EP, Maggioni C, Mezghrani A, Sitia R, Braakman I, Heck AJ Sequential waves of functionally related proteins are expressed when B cells prepare for antibody secretion. Immunity. 2003;18:243–53.CrossRefPubMed
36.
Ebato C, Uchida T, Arakawa M, Komatsu M, Ueno T, Komiya K, Azuma K, Hirose T, Tanaka K, Kominami E, Kawamori R, Fujitani Y, Watada H Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell Metab. 2008;8:325–32.CrossRefPubMed
37.
Pengo N, Scolari M, Oliva L, Milan E, Mainoldi F, Raimondi A, Fagioli C, Merlini A, Mariani E, Pasqualetto E, Orfanelli U, Ponzoni M, Sitia R, Casola S, Cenci S Plasma cells require autophagy for sustainable immunoglobulin production. Nat Immunol. 2013;14:298–305.CrossRefPubMed
38.
Arnold J, Murera D, Arbogast F, Fauny JD, Muller S, Gros F Autophagy is dispensable for B-cell development but essential for humoral autoimmune responses. Cell Death Differ. 2015. doi:10.​1038/​cdd.​2015.​149.PubMed
39.
Riz I, Hawley TS, Hawley RG KLF4-SQSTM1/p62-associated prosurvival autophagy contributes to carfilzomib resistance in multiple myeloma models. Oncotarget. 2015;6:14814–31.CrossRefPubMedPubMedCentral
40.
Vogl DT, Stadtmauer EA, Tan KS, Heitjan DF, Davis LE, Pontiggia L, Rangwala R, Piao S, Chang YC, Scott EC, Paul TM, Nichols CW, Porter DL, Kaplan J, Mallon G, Bradner JE, Amaravadi RK Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy. 2014;10:1380–90.CrossRefPubMedPubMedCentral
41.
Shimobayashi M, Hall MN Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol. 2014;15:155–62.CrossRefPubMed
42.
Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J Tuberous sclerosis complex-1 and −2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci U S A. 2002;99:13571–6.CrossRefPubMedPubMedCentral
43.
Limon JJ, So L, Jellbauer S, Chiu H, Corado J, Sykes SM, Raffatellu M, Fruman DA mTOR kinase inhibitors promote antibody class switching via mTORC2 inhibition. Proc Natl Acad Sci U S A. 2014;111:E5076–85.CrossRefPubMedPubMedCentral
44.
Benhamron S, Pattanayak SP, Berger M, Tirosh B mTOR activation promotes plasma cell differentiation and bypasses XBP-1 for immunoglobulin secretion. Mol Cell Biol. 2015;35:153–66.CrossRefPubMedPubMedCentral
45.
M. Minnich, H. Tagoh, P. Bonelt, E. Axelsson, M. Fischer, B. Cebolla, A. Tarakhovsky, S.L. Nutt, M. Jaritz, M. Busslinger, Multifunctional role of the transcription factor Blimp-1 in coordinating plasma cell differentiation. Nat Immunol. 2016:17(3):331–343
46.
Narita M, Young AR, Arakawa S, Samarajiwa SA, Nakashima T, Yoshida S, Hong S, Berry LS, Reichelt S, Ferreira M, Tavare S, Inoki K, Shimizu S Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science. 2011;332:966–70.CrossRefPubMedPubMedCentral
47.
P. Shen, T. Roch, V. Lampropoulou, R.A. O’Connor, U. Stervbo, E. Hilgenberg, S. Ries, V.D. Dang, Y. Jaimes, C. Daridon, R. Li, L. Jouneau, P. Boudinot, S. Wilantri, I. Sakwa, Y. Miyazaki, M.D. Leech, R.C. McPherson, S. Wirtz, M. Neurath, K. Hoehlig, E. Meinl, A. Grutzkau, J.R. Grun, K. Horn, A.A. Kuhl, T. Dorner, A. Bar-Or, S.H. Kaufmann, S.M. Anderton, S. Fillatreau, IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases, Nature, 507 (2014) 366–370.
Metadata
Title
Metabolic Control of Plasma Cell Differentiation- What We Know and What We Don't Know
Authors
Michael Aronov
Boaz Tirosh
Publication date
01-05-2016
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue Special Issue 1/2016
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-016-0246-9

Other articles of this Special Issue 1/2016

Journal of Clinical Immunology 1/2016 Go to the issue

OriginalPaper

Autophagy in Plasma Cell Ontogeny and Malignancy

OriginalPaper

New Insights into IL-10 Dependent and IL-10 Independent Mechanisms of Regulatory B Cell Immune Suppression

OriginalPaper

Next Generation Sequencing Data Analysis in Primary Immunodeficiency Disorders – Future Directions

OriginalPaper

Current Status: Site-Specific Antibody Drug Conjugates

Erratum

Erratum to: The Elements Steering Pathogenesis in IgG-Mediated Alloimmune Diseases

OriginalPaper

Human T Follicular Helper Cells in Primary Immunodeficiency: Quality Just as Important as Quantity
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits