Cul5: immune cell function and therapeutic potential

A primary function of immune cells is to protect against pathogens. To do this, cells surveil the body using receptors on their surface that can detect antigens from the invading organism or sense cytokines that act as danger signals. These receptors activate transcriptional programs that allow the cells to mount a response appropriate for the pathogen detected. To rapidly switch into an activated state, or to return to homeostasis, immune cells must initiate and terminate signaling pathways. Immune cells use post-transcriptional regulatory processes as one means to quickly change cellular behavior. This can be mediated by kinases and phosphatases that turn signaling pathways on or off. An additional important mechanism for downregulating immune effector cells is mediated by E3 ubiquitin ligases (E3s), which promote the degradation of receptors and their downstream signaling mediators. Ubiquitin ligases are enzymes that add ubiquitin modifications to specific protein substrates, targeting them for degradation via recruitment to the proteasome or altering their localization and activity. Cullin 5 (Cul5) is a scaffold protein that forms a multiprotein complex called Cullin Ring Ligase 5 (CRL5). To select substrates, CRL5 engages with Suppressors of Cytokine Signaling (SOCS)-box containing proteins. Collaborating with different SOCS-box containing substrate receptors allows Cul5 to promote selected protein degradation in a cell type- and context-specific manner. CRL5 and SOCS-box containing proteins regulate cytokine signaling to control proliferation, differentiation and immune functions in various cell types. Here, we give an overview of the ubiquitin proteasome system (UPS) and review new insights that advance our understanding of how Cul5 and CRL5 complexes regulate immune cell function. We then discuss ongoing therapeutic strategies that target various components of the UPS, and highlight the potential for new therapies targeting CRL5 for a range of diseases.