Hematopoietic stem cell regulation by the proteostasis network

Abstract

Purpose of review: Protein homeostasis (proteostasis) is maintained by an integrated network of physiological mechanisms and stress response pathways that regulate the content and quality of the proteome. Maintenance of cellular proteostasis is key to ensuring normal development, resistance to environmental stress, coping with infection, and promoting healthy aging and lifespan. Recent studies have revealed that several proteostasis mechanisms can function in a cell-type-specific manner within hematopoietic stem cells (HSCs). Here, we review recent studies demonstrating that the proteostasis network functions uniquely in HSCs to promote their maintenance and regenerative function.

Recent findings: The proteostasis network is regulated differently in HSCs as compared with restricted hematopoietic progenitors. Disruptions in proteostasis are particularly detrimental to HSC maintenance and function. These findings suggest that multiple aspects of cellular physiology are uniquely regulated in HSCs to maintain proteostasis, and that precise control of proteostasis is particularly important to support life-long HSC maintenance and regenerative function.

Summary: The proteostasis network is uniquely configured within HSCs to promote their longevity and hematopoietic function. Future work uncovering cell-type-specific differences in proteostasis network configuration, integration, and function will be essential for understanding how HSCs function during homeostasis, in response to stress, and in disease.

Figure 1.. Schematic of the proteostasis network.

Proteostasis is maintained by an integrated network of physiological mechanisms and stress response pathways that regulate the content and quality of the proteome. Misfolded proteins can arise from errors in translation, protein misfolding, and protein damage. Stress response pathways sense and mitigate the accumulation of misfolded and/or aggregated proteins. Terminally misfolded and aggregated proteins can be eliminated through degradation, via the ubiquitin-proteasome system or autophagy-lysosome system.

Figure 2.. HSCs depend on low protein synthesis.

A) HSCs exhibit low rates of protein synthesis and require tight control of protein synthesis. A modest decrease in the rate of translation impairs regenerative activity, whereas a modest increase in the rate of protein synthesis impairs HSC function and maintenance. B) Reduced ribosome biogenesis, hypophosphorylation of 4E-BPs, and tiRNA production contribute to attenuation of protein synthesis in HSCs. Runx1 deficiency reduces ribosome biogenesis and global rates of protein translation. mTOR signaling inactivates 4E-BPs to promotoe the initiation o cap-dependent translation. Angiogenin produced in the bone marrow microenvironment promotes production of tiRNA, which can suppress translation within HSCS. C) Increasing protein synthesis increases promotes the accumulation of unfolded/misfolded proteins that can overload the proteasome, leading to a block in the degradation of proteins that are normally turned over by the proteasome (dashed line), including c-Myc. In HSCs, stabilization of c-Myc results in increased proliferation and loss of self-renewal.

Figure 3.. Protein degradation mechanisms promote HSC self-renewal.

A) Ubiquitin ligases mark the key HSC regulators Stat5, N-myc, c-Myc, Hif-1α, and p53 for degradation by the proteasome. Stabilization or degradation of these target proteins in the absence of the ubiquitin ligases impairs HSC function. B) Core autophagy proteins support multi-lineage reconstitution, self-renewal, quiescence, and maintain HSC numbers. Pharmacological induction of autophagy also maintains HSCs ex vivo and stimulates erythropoiesis. Inhibition of lysosomal acidification induces quiescence, and the asymmetrical inheritance of lysosomes is associated with quiescence.

Figure 4.. Unfolded protein responses promote HSC function during homeostasis and in response to stress.

A) Induction of the UPR^Mito supports HSC quiescence and prevents myeloid skewing. B) The UPR^ER is induced under homeostatic and severe levels of stress. Activation of the Ire1 and Perk branches of the UPR^ER promote HSC survival during homeostasis whereas activation of Perk can also induce apoptosis during severe stress to uphold the integrity of the HSC pool. Activation of Ire1 and Perk support survival and recovery of HSCs after transplantation and Ire1 promotes reconstitution capacity.