Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence

Abstract

Graphical Abstract Highlights d The endogenous polyamine spermidine maintains autophagy via hypusinating eIF5A d Hypusinated translation factor eIF5A controls TFEB expression and autophagy d Spermidine restores B cell responses in old mice and humans d TFEB levels decline with age and can be used as drug target/ biomarker for human aging SUMMARYFailure 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.

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

“…EIF5A also regulates mitochondrial respiration via initiation from alternative start codons. In addition, EIF5A restricts RNA virus infections [22, 55, 64, 78, 101, 110, 112, 113, 125, 148, 152, 164, 235]. It is important to note in this context that ATXN2 is cleaved by Coxsackie-virus and Polio-virus, during their optimized efforts to diminish host cell defenses against invading viral RNA [84].…”

Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics

“…Spermidine is an important polyamine capable of inducing autophagy ( 21 ) and responsible for hypusination of the eukaryotic translation initiation factor eIF5A ( 22 ). eIF5A activates the autophagy transcription factor TFEB and regulates proteins responsible for mitochondrial respiration ( 23 ).…”

Autophagy in T cells from aged donors is maintained by spermidine, and correlates with function and vaccine responses

“…We have recently shown that treating old but not young mice with the metabolite spermidine improves autophagy levels in B lymphocytes due to an age-related decline of endogenous spermidine 15 . Here we sought to confirm this in human lymphocytes.…”

“…Several downstream mechanisms of spermidine-induced autophagy have been described in mice, including the inhibition of histone deacetylases 14 . Recently we uncovered a novel pathway in which spermidine lends a residue for the hypusination of the translation factor eIF5a, which is necessary for the translation of a three proline motif present in the master transcription factor of autophagy and lysosomal biogenesis, called TFEB 15 . We demonstrated this pathway operates in activated B cells, which upon activation have an unusually high protein synthesis rate, owing to the high production of immunoglobulins.…”