CD109, a master regulator of inflammatory responses

Abstract

Inflammation is a complex response to harmful stimuli, crucial for immunity, and linked to chronic diseases and cancer, with TGF-β and NF-κB pathways as key regulators. CD109 is a glycosylphosphatidylinositol (GPI)-anchored protein, that our group has originally identified as a TGF-β co-receptor and inhibitor of TGF-β signaling. CD109 modulates TGF-β and NF-κB pathways, to influence immune responses and inflammation. CD109's multifaceted role in inflammation spans various tissue types, including the skin, lung, bone and bone-related tissues, and various types of cancers. CD109 exerts its effects by modulating processes such as cytokine secretion, immune cell recruitment, macrophage polarization, T helper cell function and cancer cell phenotype and function. Here, we review CD109's regulatory functions in inflammatory responses in these various tissues and cell types. Exploration of CD109's mechanisms of action will enhance our understanding of its contributions to disease pathology and its potential for therapeutic applications.

Keywords: CD109; NF-κB signaling; TGF-β signaling; inflammatory response; pathway crosstalk.

Figure 1

Overview of CD109-mediated regulation of TGF-β and NF-κB signaling. (A) The canonical NF-κB pathway is activated by receptors such as TCRs, TLRs, and TNFRs. Ligand binding to these receptors activates IKKs to phosphorylate IκB. Phosphorylated IκB dissociates from the NF-κB complex (p50 and p65/RelA), gets polyubiquitinated, and is degraded. The p50/p65 complex then translocates to the nucleus to activate immune response genes. (B) In the canonical TGF-β signaling, when TGF-β binds to the TGF-β Receptor I and II complex, it leads to the phosphorylation of Smad2/3. The activated Smad2/3 then form a complex with Smad4 and translocate to the nucleus to regulate the transcription of target genes. Smad7 can inhibit TGF-β signaling by either preventing Smad2/3 phosphorylation or by inhibiting the transcriptional activity of the nuclear Smad complex. (C) The TGF-β and NF-κB canonical pathways crosstalk with each other through various mechanisms.TGF-β can activate TAK1 and TBK1, which in turn activate the IKK complex and promote NF-κB signaling.The p65 subunit can enhance Smad7 expression, inhibiting TGF-β signaling. Additionally, p65 can enable Smad7 to bind to TAB2/3, inhibiting TNF-α receptor activation, reducing inflammatory responses. CD109 inhibits canonical TGF-β signaling. The specific role of CD109 in the canonical NF-κB pathway and its crosstalk with the TGF-β pathway remains unclear. The red circles and dashed arrows with a question mark indicate targets potentially regulated by CD109. TCR: T Cell Receptor; TLR: Toll-Like Receptor; TNFR: TNF-α Receptor; TβRI/II: TGF-β Receptor I/II; IκB: Inhibitor of NF-κB; IKK: IκB kinases; TAB2/3: TGF-β Activated Kinase Binding Proteins 2 and 3; TAK1: TGF-β-Activated Kinase 1; TBK: TANK-binding Kinase. Created with BioRender.com .

Figure 2

Role of CD109 in regulating immune and inflammatory responses in various tissues and cell types: The schematic diagram depicts tissues and cell types where CD109 is known to regulate immune and inflammatory responses. Created with BioRender.com .