Sorting nexin 5 mediates virus-induced autophagy and immunity

Abstract

Autophagy, a lysosomal degradation pathway, plays an essential role in multiple aspects of immunity, including immune system development, regulation of innate and adaptive immune and inflammatory responses, selective degradation of intracellular microbes, and host protection against infectious diseases 1 , 2 . Unlike autophagy induction by stimuli such as nutrient deprivation and mTOR suppression, little is known about how autophagosomal biogenesis is initiated in mammalian cells in response to viral infection. We performed genome-wide siRNA screens and found that the endosomal protein sorting nexin 5 (SNX5) 3 , 4 is essential for virus-induced, but not for basal, stress- or endosome-induced, autophagy. We showed that SNX5 deletion increases cellular susceptibility to viral infection in vitro , and that Snx5 knockout in mice enhances lethality after infection with multiple human viruses. Mechanistically, SNX5 interacts with beclin 1 and ATG14-containing Class III phosphatidylinositol 3-kinase (PI3KC3) complex 1 (PI3KC3-C1), increases the lipid kinase activity of purified PI3KC3-C1, and is required for endosomal generation of PI3P and recruitment of the PI3P-binding protein WIPI2 to virion-containing endosomes. These findings identify a context- and organelle-specific mechanism – SNX5-dependent PI3KC3-C1 activation at endosomes – for autophagy initiation during viral infection.

AQP3‐mediated H2O2 uptake inhibits LUAD autophagy by inactivating PTEN

“…Autophagy is inhibited by the hyperactivation of AKT/mTOR signaling 15,16 . Therefore, we investigated the influence of H 2 O 2 on autophagy in LUAD cells and observed that H 2 O 2 at a proliferative concentration suppressed rapamycin (Rapa)‐induced autophagy, which could be counteracted by AQP3 depletion.…”

“…Autophagy is inhibited by the hyperactivation of AKT/mTOR signaling. 15 , 16 Therefore, we investigated the influence of H 2 O 2 on autophagy in LUAD cells and observed that H 2 O 2 at a proliferative concentration suppressed rapamycin (Rapa)‐induced autophagy, which could be counteracted by AQP3 depletion. In a tissue Microarray (TMA) containing tissues from 74 LUAD patients, we tested the relationships between AQP3, 8‐hydroxy‐2′‐deoxyguanosine (8‐oxo, an oxidative stress biomarker) and p62 (SQSTM1, an autophagosome marker).…”

Identification of novel candidate factor SNX5 specific for pregnancy failure in Holstein heifers

“…The macropinocytosis is adapted as an alternative means of nutrient source to allow sustained fetal growth, which is greatly enhanced during amino acid shortage 18, 19 . In addition, it has been reported that SNX5 stimulated autophagy during viral infection 20 . In cattle, amino acids are essential for the survival and development of embryo 14,21 .…”

Herpesvirus Regulation of Selective Autophagy

“…Intriguingly, a recent genome-wide short interfering RNA screen study showed that virion-containing endosomes can be targeted for virophagy. The endosomal protein sorting nexin 5 (SNX5) interacts with ATG14-containing class III phosphatidylinositol-3-kinase complex 1 (PI3KC3-C1) upon HSV-1 (ICP34.5 Δ68–87 ) infection and increases the lipid kinase activity of PI3KC3-C1, which in turn promotes endosomal generation of phosphatidylinositol-3-phosphate (PtdIns(3)P), and recruitment of (PtdIns(3)P)-binding protein WIPI2 to virion-containing endosomes [ 111 ].…”