Regulation of Normal and Malignant Hematopoiesis by FBOX Ubiquitin E3 Ligases

Abstract

Hematopoiesis is responsible for numerous functions, ranging from oxygen transportation to host defense, to injury repair. This process of hematopoiesis is maintained throughout life by hematopoietic stem cells and requires a controlled balance between self-renewal, differentiation, and quiescence. Disrupting this balance can result in hematopoietic malignancies, including anemia, immune deficiency, leukemia, and lymphoma. Recent work has shown that FBOX E3 ligases, a substrate recognition component of the ubiquitin proteasome system (UPS), have an integral role in maintaining this balance. In this review, we detail how FBOX proteins target specific proteins for degradation to regulate hematopoiesis through cell processes, such as cell cycle, development, and apoptosis.

Keywords: FBOX proteins; hematopoiesis; ubiquitin E3 ligases; ubiquitin proteasome system.

Figure 1. Steps of the Ubiquitin Proteasome System (UPS).

The first step of the UPS system is the activation of ubiquitin by the E1 ubiquitin ligase (1) by using ATP. Ubiquitin is then conjugated by the E2 ubiquitin ligase (2). The E3 ubiquitin ligase interacts with both the protein that is targeted for degradation and the E2 ubiquitin ligase aiding the transfer of ubiquitin onto the target substrate (3). The formation of the polyubiquitin tail signals for the target substrate to be sent to the proteasome (4) and later degraded (5). Ub= ubiquitin

Figure 2. Schematic of the SKP1-CUL1-FBOX (SCF) Complex.

The SCF Complex is primarily composed of the adaptor protein SKP1, the scaffolding protein CUL1, and the substrate recognition component, the FBOX protein. The complex also contains the ubiquitin binding RING-finger protein, RBX1, and the E2 ubiquitin ligase. The FBOX protein binds to its target substrate after it has been phosphorylated. The SCF complex allows for the transfer of ubiquitin from the E2 ubiquitin ligase onto the target substrate, producing a ubiquitin tail, and signaling the target substrate to be sent to the proteasome and degraded. Ub= ubiquitin, P= phosphate

Figure 3. FBOX proteins contribute to regulating the cell cycle in the vertebrate hematopoietic system.

Model of the cell cycle including prominent cyclin-cyclin dependent kinase (CCN-CDK) complexes as regulated by FBOX proteins either directly or via other cell cycle regulators. Activation in green, inhibition in red.

Figure 4. FBOX proteins contribute to regulating hematopoiesis in vertebrates.

Schematic of hematopoiesis including FBOX proteins known to regulate specific branches. Regulation by FBOX proteins can affect the promotion of cells through various branches of hematopoiesis as well as alter their functions, such as leading to malignancy.