ATP8b1, a PIP2 flippase and negative regulator of GsdmD cleavage.

What is it about?

Dysfunctional inflammatory immune responses to modified lipids/cholesterol and bacterial components leads to unresolved and chronic inflammation, promoting various metabolic and genetic diseases in humans. One example of disease related to dysregulated cholesterol metabolism and unresolved extrahepatic inflammation is progressive familial intrahepatic cholestasis 1 (PFIC1), where mutations in ATP8b1 (a member of the type 4 subfamily of P-type ATPases) perturbs the detergent-resistant state of the hepatic canalicular membrane, leading to hepatic injury. PFIC1 patients often present with intense pruritus, deafness, fat malabsorption, atherosclerosis, and pancreatitis. These extrahepatic manifestations suggest a role of ATP8b1 in regulating inflammation in other tissues. While much is known about the pathophysiology of PFIC1, the underlying mechanism for how the loss of ATP8b1 leads to compromised integrity of the canalicular membrane, hepatic injury, and extrahepatic inflammation is not clear. A high throughput proteomic analysis suggests that ATP8b1 flippase activity and phosphoinositide metabolism may be interconnected, but the mechanistic link between ATP8b1 and phosphatidylinositol metabolism is not clear. This work shows that ATP8b1 maintains PIP2 at the inner leaflet of the plasma membrane. ATP8b1 serves as a negative regulator of inflammasome activity via modulating cleavage of pyroptosis executor Gasdermin D (GsdmD), a pore-forming protein, involved in promoting a variety of inflammatory diseases.

Featured Image

Photo by Lanju Fotografie on Unsplash

Photo by Lanju Fotografie on Unsplash

Why is it important?

PIP2, a minor signaling phospholipid, is involved in a variety of cellular pathways, such as cell signaling, ion channel activity, protein trafficking, vesicular transport, and more recently in the GsdmD-IL-1b pathway. Despite the wide variety of physiological and pathological roles of PIP2, the protein involved in restricting PIP2 to the inner leaflet of the PM has not yet been identified. Our study fills this fundamental gap by establishing ATP8b1 as the first known PIP2 flippase from any system. Human mutations in ATP8b1 cause progressive familial intrahepatic cholestasis (PFIC1) disease and liver damage, but also show extrahepatic manifestation such as pancreatitis, hearing loss, and atherosclerosis. Even after liver transplantation, which rescues hepatic symptoms, the extrahepatic symptoms of PFIC1 persist or even worsens in some cases. These data indicate that the role of ATP8b1 in inflammation may be independent of cholestasis. This study identifies ATP8b1 is a novel inhibitor of GsdmD cleavage, leading to a new mechanistic model where ATP8b1 deletion promotes GsdmD cleavage in the presence of LPS via a caspase-11 (in mice) or caspase-4/5 (in humans) dependent non-canonical inflammasome pathway.

Perspectives