γ-Secretase fanning the fire of innate immunity

Abstract

Innate immunity is the first line of defense against pathogens, alerting the individual cell and surrounding area to respond to this potential invasion. γ-secretase is a transmembrane protease complex that plays an intricate role in nearly every stage of this innate immune response. Through regulation of pattern recognition receptors (PRR) such as TREM2 and RAGE γ-secretase can modulate pathogen recognition. γ-secretase can act on cytokine receptors such as IFNαR2 and CSF1R to dampen their signaling capacity. While γ-secretase-mediated regulated intramembrane proteolysis (RIP) can further moderate innate immune responses through downstream signaling pathways. Furthermore, γ-secretase has also been shown to be regulated by the innate immune system through cytokine signaling and γ-secretase modulatory proteins such as IFITM3 and Hif-1α. This review article gives an overview of how γ-secretase is implicated in innate immunity and the maintenance of its responses through potentially positive and negative feedback loops.

Keywords: Hif1a; IFITM3; cytokine signaling; inflammation; innate immunity; regulated intramembrane proteolysis.

Figure 1.. γ-Secretase produces Aβ peptides through amyloidogenic pathway.

The amyloidogenic pathway involves sequential cleavage of APP by β- and γ-secretase, resulting in the production of Aβ peptides and APP intracellular domain (AICD). AICD can translocate into nucleus and regulate gene expression through interactions with Fe65 and Tip60. Aβ peptides can undergo oligomerization and fibrillation, leading to the formation of extracellular amyloid plaques. Aβ accumulation can induce activation of immune cells (e.g. microglia) and drives inflammatory responses (e.g. cytokine release and phagocytosis).

Figure 2.. γ-Secretase regulates innate immunity through Notch pathway.

Activation of Notch pathway by ligand-receptor interaction leads to regulated intramembrane proteolysis of Notch receptors by γ-secretase. This generates the Notch intracellular domain (NICD), which can translocate to the nucleus and activate gene expressions (including proinflammatory cytokines) through interactions with CSL and MAM in the canonical pathway. Alternatively, NICD can interact with other signaling pathways (such as MAPK and NFkB pathways), which can also drive cytokine productions.

Figure 3.. γ-Secretase regulates inflammatory responses through the proteolysis of innate immune receptors.

γ-secretase controls the turnover of several innate immune receptors (such as RAGE, TNFR, CSF1R, TREM2) through its proteolytic activities. The intramembrane cleavage of receptors by γ-secretase leads to the termination of receptor signaling. However, the ICD released from γ-secretase cleavage may have other signaling functions that are not yet well-understood.

Figure 4.. Innate immunity modulates γ-secretase activity in contexts of neuroinflammation and hypoxia.

The activity of γ-secretase is regulated by various modulatory proteins through protein-protein interactions. In the context of viral infection and inflammation, IFITM3 is upregulated and can modulate γ-secretase activity by interacting with PS. This leads to increased cleavage of APP by γ-secretase, while Notch processing is reduced. On the other hand, in hypoxia, HIF1-α modulates γ-secretase activity and stimulates the proteolytic processing of both APP and Notch.

Figure 5.. A graphic summary: γ-secretase at the center of the innate immunity.

γ-secretase plays a critical role in regulating many aspects of innate immune responses, including pathogen recognition and cytokine signaling. While γ-secretase is also regulated by innate immunity through modulatory proteins, such as IFITM3 and HIF-1α.