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The role of autophagy in plasma cell ontogenesis.

Pengo N, Cenci S - Autophagy (2013)

Bottom Line: We have identified in plasma cells a novel ATG5-dependent selective negative control on the secretory pathway, which restricts antibody production, sustaining energy metabolism.Revealing new immune functions, autophagy is required in vivo for antibody responses and to maintain the memory plasma cell compartment.

View Article: PubMed Central - PubMed

Affiliation: MRC LMCB, University College London, London, UK.

ABSTRACT
We have identified in plasma cells a novel ATG5-dependent selective negative control on the secretory pathway, which restricts antibody production, sustaining energy metabolism. Revealing new immune functions, autophagy is required in vivo for antibody responses and to maintain the memory plasma cell compartment.

Show MeSH
Figure 1. An autophagy-dependent cytoprotective trade-off between Ig synthesis and viability in PC ontogenesis. Autophagy limits ER expansion under pharmacological stress in yeast. We found a similar regulation in mammalian physiology: an ATG5-dependent negative control of the ER in PCs, which discloses a novel mechanism and an unanticipated immune function for autophagy. (A) During PC differentiation, autophagy restricts the secretory capacity, reducing ER stress signaling and the expression of the PC key transcriptional regulators, sXBP-1 (spliced form of XBP-1) and PRDM1/Blimp-1, as well as the production of antibodies, while sustaining ATP and viability. (B) Autophagy is essential in PC ontogenesis. Previously shown to be involved in early B cell development (1), but dispensable for the maintenance of most mature B cells (2), we now prove autophagy necessary for T-independent (3) and T-dependent (4) primary antibody responses. Moreover, we find autophagy dispensable in germinal center (GC) B cells (5), but required to maintain the long-lived memory PC pool in the BM (6). Thus, our study proves autophagy essential across PC ontogenesis.
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Figure 1: Figure 1. An autophagy-dependent cytoprotective trade-off between Ig synthesis and viability in PC ontogenesis. Autophagy limits ER expansion under pharmacological stress in yeast. We found a similar regulation in mammalian physiology: an ATG5-dependent negative control of the ER in PCs, which discloses a novel mechanism and an unanticipated immune function for autophagy. (A) During PC differentiation, autophagy restricts the secretory capacity, reducing ER stress signaling and the expression of the PC key transcriptional regulators, sXBP-1 (spliced form of XBP-1) and PRDM1/Blimp-1, as well as the production of antibodies, while sustaining ATP and viability. (B) Autophagy is essential in PC ontogenesis. Previously shown to be involved in early B cell development (1), but dispensable for the maintenance of most mature B cells (2), we now prove autophagy necessary for T-independent (3) and T-dependent (4) primary antibody responses. Moreover, we find autophagy dispensable in germinal center (GC) B cells (5), but required to maintain the long-lived memory PC pool in the BM (6). Thus, our study proves autophagy essential across PC ontogenesis.

Mentions: The unexpected physiological downregulation of ER capacity and Ig production driven by autophagy defines a novel ATG5-dependent ER homeostatic circuitry. However, it raises the question as to what advantage accrues from such a strong induction of autophagy in PCs. The benefit became evident when we measured intracellular ATP, whose levels dropped in atg5–/– PCs. Thus, the intense metabolic demand of synthesizing antibodies requires functional autophagy, even if this results in lower secretory potential. Indeed, lack of autophagy is toxic to PCs, causing a substantial increase in cell death, as assessed in vitro. Hence, autophagy in PCs serves the dual function of limiting ER capacity and Ig output, while promoting energy metabolism and survival (Fig. 1A).


The role of autophagy in plasma cell ontogenesis.

Pengo N, Cenci S - Autophagy (2013)

Figure 1. An autophagy-dependent cytoprotective trade-off between Ig synthesis and viability in PC ontogenesis. Autophagy limits ER expansion under pharmacological stress in yeast. We found a similar regulation in mammalian physiology: an ATG5-dependent negative control of the ER in PCs, which discloses a novel mechanism and an unanticipated immune function for autophagy. (A) During PC differentiation, autophagy restricts the secretory capacity, reducing ER stress signaling and the expression of the PC key transcriptional regulators, sXBP-1 (spliced form of XBP-1) and PRDM1/Blimp-1, as well as the production of antibodies, while sustaining ATP and viability. (B) Autophagy is essential in PC ontogenesis. Previously shown to be involved in early B cell development (1), but dispensable for the maintenance of most mature B cells (2), we now prove autophagy necessary for T-independent (3) and T-dependent (4) primary antibody responses. Moreover, we find autophagy dispensable in germinal center (GC) B cells (5), but required to maintain the long-lived memory PC pool in the BM (6). Thus, our study proves autophagy essential across PC ontogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 1: Figure 1. An autophagy-dependent cytoprotective trade-off between Ig synthesis and viability in PC ontogenesis. Autophagy limits ER expansion under pharmacological stress in yeast. We found a similar regulation in mammalian physiology: an ATG5-dependent negative control of the ER in PCs, which discloses a novel mechanism and an unanticipated immune function for autophagy. (A) During PC differentiation, autophagy restricts the secretory capacity, reducing ER stress signaling and the expression of the PC key transcriptional regulators, sXBP-1 (spliced form of XBP-1) and PRDM1/Blimp-1, as well as the production of antibodies, while sustaining ATP and viability. (B) Autophagy is essential in PC ontogenesis. Previously shown to be involved in early B cell development (1), but dispensable for the maintenance of most mature B cells (2), we now prove autophagy necessary for T-independent (3) and T-dependent (4) primary antibody responses. Moreover, we find autophagy dispensable in germinal center (GC) B cells (5), but required to maintain the long-lived memory PC pool in the BM (6). Thus, our study proves autophagy essential across PC ontogenesis.
Mentions: The unexpected physiological downregulation of ER capacity and Ig production driven by autophagy defines a novel ATG5-dependent ER homeostatic circuitry. However, it raises the question as to what advantage accrues from such a strong induction of autophagy in PCs. The benefit became evident when we measured intracellular ATP, whose levels dropped in atg5–/– PCs. Thus, the intense metabolic demand of synthesizing antibodies requires functional autophagy, even if this results in lower secretory potential. Indeed, lack of autophagy is toxic to PCs, causing a substantial increase in cell death, as assessed in vitro. Hence, autophagy in PCs serves the dual function of limiting ER capacity and Ig output, while promoting energy metabolism and survival (Fig. 1A).

Bottom Line: We have identified in plasma cells a novel ATG5-dependent selective negative control on the secretory pathway, which restricts antibody production, sustaining energy metabolism.Revealing new immune functions, autophagy is required in vivo for antibody responses and to maintain the memory plasma cell compartment.

View Article: PubMed Central - PubMed

Affiliation: MRC LMCB, University College London, London, UK.

ABSTRACT
We have identified in plasma cells a novel ATG5-dependent selective negative control on the secretory pathway, which restricts antibody production, sustaining energy metabolism. Revealing new immune functions, autophagy is required in vivo for antibody responses and to maintain the memory plasma cell compartment.

Show MeSH