Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence
Authors: Jack Feltham
Thomas Riffelmacher
Gennaro Napolitano
Philip Charles
Stefan Balabanov
Zhanru Yu
Hanlin Zhang
Shabaz Mohammed
Yizhe Sun
Ghada Alsaleh
Philip Hublitz
Anna Katharina Simon
Lisa Frau
Jane Mellor
Andrea Ballabio
Journal: Molecular cell (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: B cell; TFEB; aging; autophagy; eIF5A
Affiliations: The Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, OX3 7FY, UK., Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy; Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Via Pansini 5, 80131, Naples, Italy., Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK; Target Discovery Institute, University of Oxford, Roosevelt Drive, Oxford, OX3 7FZ, UK., MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK., Target Discovery Institute, University of Oxford, Roosevelt Drive, Oxford, OX3 7FZ, UK., Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy; Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Via Pansini 5, 80131, Naples, Italy; Department of Molecular and Human Genetics and Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA., Division of Haematology, University Hospital and University of Zürich, 8091, Zürich, Switzerland., The Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, OX3 7FY, UK. Electronic address: .

Abstract:  Failure to make adaptive immune responses is a hallmark of aging. Reduced B cell function leads to poor vaccination efficacy and a high prevalence of infections in the elderly. Here we show that reduced autophagy is a central molecular mechanism underlying immune senescence. Autophagy levels are specifically reduced in mature lymphocytes, leading to compromised memory B cell responses in old individuals. Spermidine, an endogenous polyamine metabolite, induces autophagy in vivo and rejuvenates memory B cell responses. Mechanistically, spermidine post-translationally modifies the translation factor eIF5A, which is essential for the synthesis of the autophagy transcription factor TFEB. Spermidine is depleted in the elderly, leading to reduced TFEB expression and autophagy. Spermidine supplementation restored this pathway and improved the responses of old human B cells. Taken together, our results reveal an unexpected autophagy regulatory mechanism mediated by eIF5A at the translational level, which can be harnessed to reverse immune senescence in humans. 

Retracted: No

PubPeer comments:
 Readers should become aware of a recent paper published in JBC showing that autophagy induction by exogenous polyamines (including spermidine and spermine) is an artifact of BSA oxidase activity in culture serum. https: www.jbc.org content early 2020 05 19 jbc.RA120.013867.abstract From the article:  Consequently, considerable caution must be used when interpreting much of the published mechanistic data produced in in vitro cell culture systems as any observed autophagy included in such systems is likely the result of the toxic metabolites formed by BSAO following polyamines addition to the serum-containing medium and not a function of the polyamines themselves , 
 Dear Dr Rothii Thank you for pointing this new paper out to us. While carrying out the research for our paper in Mol Cell, 2019, we also noticed non-specific and toxic effects of Spermidine (please see supplementary figures). Here is how we excluded these for our main findings: First, we observed that excess spermidine (100 uM or higher) induces cellular stress responses and death in cultured cells in an eIF5A-independent manner (shown in supplementary figure S3). While we did not know the exact mechanism for this, the oxidation of spermidine provides a good explanation. We used lower spermidine concentrations in subsequent experiments (10uM or less). Second, autophagy was suppressed when we pharmacologically or genetically inhibited spermidine production or eIF5A hypusination, thereby excluding the issue with spermidine oxidation. Third, we found that low-dose (1uM) spermidine administration rescues intracellular spermidine levels and eIF5A hypusination levels in spermidine-depleted cells, indicating that at least some spermidine can be taken up by cells and perform its physiological role. Low-dose spermidine treatment did not induce cell death in our systems. Fourthly, while adding spermidine to B cells obtained from old mice or human donors in which spermidine and autophagy levels are low, increased autophagy and other functions, we did not achieve this in B cells from young mice donors, suggesting that oxidised spermidine is not responsible for this increase in autophagy levels (supplementary figure 7). Lastly many of our experiments on B cell function were also carried out in vivo. ,