美国加州大学圣地亚哥分校Robert A.J. Signer团队近期取得重要工作进展，他们研究发现造血干细胞优先将错误折叠的蛋白质运输到聚集体并依赖聚集体来维持蛋白质稳态。相关研究成果2023年3月21日在线发表于《细胞—干细胞》杂志上。

据介绍，造血干细胞（HSC）在整个生命过程中再生血细胞。为了保持健康，HSC特别依赖于维持蛋白质稳态（proteostasis）。然而，造血干细胞如何清除错误折叠的蛋白质尚不清楚。

研究人员发现，与大多数主要利用蛋白酶体降解错误折叠蛋白的细胞相比，HSC优先以Bag3依赖的方式将错误折叠的蛋白输送到聚集蛋白体，并依赖于聚集蛋白吞噬（一种选择性的自噬形式）在体内维持蛋白稳定。当自噬被阻断时，HSC通过增加蛋白酶体活性进行补偿，但随着蛋白质聚集体的积累和HSC功能的受损，蛋白稳定平衡最终被破坏。Bag3缺乏会减弱HSC中聚集体的形成，导致蛋白质聚集体积累、骨髓偏向分化和自我更新活性降低。

此外，HSC衰老与聚集体的严重丧失和自噬流量的减少有关。因此，蛋白质降解途径在年轻成人HSC中被专门配置，以保持蛋白稳定和适应性，但在衰老过程中变得失调。

附：英文原文

Title: Hematopoietic stem cells preferentially traffic misfolded proteins to aggresomes and depend on aggrephagy to maintain protein homeostasis

Author: Bernadette A. Chua, Connor J. Lennan, Mary Jean Sunshine, Daniela Dreifke, Ashu Chawla, Eric J. Bennett, Robert A.J. Signer

Issue&Volume: 2023-03-21

Abstract: Hematopoietic stem cells (HSCs) regenerate blood cells throughout life. To preserve their fitness, HSCs are particularly dependent on maintaining protein homeostasis (proteostasis). However, how HSCs purge misfolded proteins is unknown. Here, we show that in contrast to most cells that primarily utilize the proteasome to degrade misfolded proteins, HSCs preferentially traffic misfolded proteins to aggresomes in a Bag3-dependent manner and depend on aggrephagy, a selective form of autophagy, to maintain proteostasis in vivo. When autophagy is disabled, HSCs compensate by increasing proteasome activity, but proteostasis is ultimately disrupted as protein aggregates accumulate and HSC function is impaired. Bag3-deficiency blunts aggresome formation in HSCs, resulting in protein aggregate accumulation, myeloid-biased differentiation, and diminished self-renewal activity. Furthermore, HSC aging is associated with a severe loss of aggresomes and reduced autophagic flux. Protein degradation pathways are thus specifically configured in young adult HSCs to preserve proteostasis and fitness but become dysregulated during aging.

DOI: 10.1016/j.stem.2023.02.010

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00071-1