Thioredoxin-interacting protein regulates haematopoietic stem cell ageing and rejuvenation by inhibiting p38 kinase activity

Abstract

Ageing is a natural process in living organisms throughout their lifetime, and most elderly people suffer from ageing-associated diseases. One suggested way to tackle such diseases is to rejuvenate stem cells, which also undergo ageing. Here we report that the thioredoxin-interacting protein (TXNIP)-p38 mitogen-activated protein kinase (p38) axis regulates the ageing of haematopoietic stem cells (HSCs), by causing a higher frequency of long-term HSCs, lineage skewing, a decrease in engraftment, an increase in reactive oxygen species and loss of Cdc42 polarity. TXNIP inhibits p38 activity via direct interaction in HSCs. Furthermore, cell-penetrating peptide (CPP)-conjugated peptide derived from the TXNIP-p38 interaction motif inhibits p38 activity via this docking interaction. This peptide dramatically rejuvenates aged HSCs in vitro and in vivo. Our findings suggest that the TXNIP-p38 axis acts as a regulatory mechanism in HSC ageing and indicate the potent therapeutic potential of using CPP-conjugated peptide to rejuvenate aged HSCs.

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

“…However, the interaction of TXNIP and AKT was upregulated by glucose and H 2 O 2 treatment (Figure 3), implying that TXNIP may negatively regulate AKT activity under glucose stress and oxidative stress. We previously reported that TXNIP deficiency induced premature aging phenotypes of HSCs in aged mice by increasing ROS levels in vitro and in vivo (Jung et al, 2016, 2013 ). Next, we analyzed the metabolic characterization of WT and KO mice to determine the effect of TXNIP on the aging of mice.…”

“…In our previous reports, we found that TXNIP interacts with p53, p38 MAPK, and macrophage migration inhibitory factor (MIF) and regulates their functional activity (Jung et al, 2016, 2013; Kim et al, 2017). TXNIP stabilized p53 protein via direct interaction, and TXNIP acted as a functional switch of p53 to regulate ROS level in hematopoietic cells.…”

“…TXNIP ‐/‐ mice (C57BL/6) were generated and were genotyped as previously reported (Jung et al, 2016). Akita mice were obtained from Dr. Chul‐Ho Lee (KRIBB, Korea).…”

“…TXNIP is an α‐arrestin family protein that is induced by a rise in glucose and oxidative stress and is known to be a tumor suppressor and inhibit thioredoxin (TRX), an antioxidant protein, via a direct interaction (DeBalsi et al, 2014; Jung et al, 2016, 2013 ). Many studies have examined the role of TXNIP in glucose uptake and metabolism.…”

“…TXNIP expression is related to mitochondrial fuel switching under conditions of starvation, diabetes, and exercise in skeletal muscle (DeBalsi et al, 2014). Previously, we suggested that TXNIP is highly expressed and acts as an antioxidant protein to regulate cellular ROS by activating p53 activity or by inhibiting p38 mitogen‐activated protein kinase (MAPK) activity via direct interaction in hematopoietic stem cells (HSCs) (Jung & Choi, 2014; Jung et al, 2016, 2013 ). Importantly, TXNIP‐deficient mice are more glucose‐tolerant than wild‐type (WT) mice (Hui et al, 2008).…”