Shigella phagocytic vacuolar membrane remnants participate in the cellular response to pathogen invasion and are regulated by autophagy

Intracellular pathogens like Shigella flexneri enter host cells by phagocytosis. Once inside, the pathogen breaks the vacuolar membrane for cytosolic access. The fate and function of the vacuolar membrane remnants are not clear. Examining Shigella-infected nonmyeloid cells, we observed that proteins associated with vacuolar membrane remnants are polyubiquinated, recruit the autophagy marker LC3 and adaptor p62, and are targeted to autophagic degradation. Further, inflammasome components and caspase-1 were localized to these membranes and correlated with dampened inflammatory response and necrotic cell death. In Atg4B mutant cells in which autophagosome maturation is blocked, polyubiquitinated proteins and P62 accumulated on membrane remnants, and as in autophagy-deficient Atg5(-/-) cells, the early inflammatory and cytokine response was exacerbated. Our results suggest that host membranes, after rupture by an invading cytoplasm-targeted bacterium, contribute to the cellular responses to infection by acting as a signaling node, with autophagy playing a central role in regulating these responses.

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Nicolas Dupont, Françoise Gisou van der Goot Grunberg
2009
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https://infoscience.epfl.ch/record/150166?ln=fr

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Autophagy Defect Is Associated with Low Glucose-Induced Apoptosis in 661W Photoreceptor Cells

Pénélope Andreux, Johan Auwerx, Martine Emery

Glucose is an important metabolic substrate of the retina and diabetic patients have to maintain a strict normoglycemia to avoid diabetes secondary effects, including cardiovascular disease, nephropathy, neuropathy and retinopathy. Others and we recently demonstrated the potential role of hypoglycemia in diabetic retinopathy. We showed acute hypoglycemia to induce retinal cell death both in vivo during an hyperinsulinemic/hypoglycemic clamp and in vitro in 661W photoreceptor cells cultured at low glucose concentration. In the present study, we showed low glucose to induce a decrease of BCL2 and BCL-XL anti-apoptotic proteins expression, leading to an increase of free pro-apoptotic BAX. In parallel, we showed that, in retinal cells, low glucose-induced apoptosis is involved in the process of autophagosomes formation through the AMPK/RAPTOR/mTOR pathway. Moreover, the decrease of LAMP2a expression led to a defect in the autophagosome/lysosome fusion process. Specific inhibition of autophagy, either by 3-methyladenine or by down-regulation of ATG5 or ATG7 proteins expression, increased caspase 3 activation and 661W cell death. We show that low glucose modifies the delicate equilibrium between apoptosis and autophagy. Cells struggled against low nutrient condition-induced apoptosis by starting an autophagic process, which led to cell death when inhibited. We conclude that autophagy defect is associated with low glucose-induced 661W cells death that could play a role in diabetic retinopathy. These results could modify the way of addressing negative effects of hypoglycemia. Short-term modulation of autophagy could be envisioned to treat diabetic patients in order to avoid secondary complications of the disease.

Public Library of Science2013

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Infrared and 2-Dimensional Correlation Spectroscopy Study of the Effect of CH3NH3PbI3 and CH3NH3SnI3 Photovoltaic Perovskites on Eukaryotic Cells

Ryma Iness Benmessaoud, László Forró, Endre Horvath

We studied the effect of the exposure of human A549 and SH-SY5Y cell lines to aqueous solutions of organic/inorganic halide perovskites CH3NH3PbI3 (MAPbI3) and CH3NH3SnI3 (MASnI3) at the molecular level by using Fourier transform infrared microspectroscopy. We monitored the infrared spectra of some cells over a few days following exposure to the metals and observed the spectroscopic changes dominated by the appearance of a strong band at 1627 cm−1. We used Infrared (IR) mapping to show that this change was associated with the cell itself or the cellular membrane. It is unclear whether the appearance of the 1627 cm−1 band and heavy metal exposure are related by a direct causal relationship. The spectroscopic response of exposure to MAPbI3 and MASnI3 was similar, indicating that it may arise from a general cellular response to stressful environmental conditions. We used 2D correlation spectroscopy (2DCOS) analysis to interpret spectroscopic changes. In a novel application of the method, we demonstrated the viability of 2DCOS for band assignment in spatially resolved spectra. We assigned the 1627 cm−1 band to the accumulation of an abundant amide or amine containing compound, while ruling out other hypotheses. We propose a few tentative assignments to specific biomolecules or classes of biomolecules, although additional biochemical characterization will be necessary to confirm such assignments

2020

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Diverse roles of TssA-like proteins in the assembly of bacterial type VI secretion systems

Sergey Nazarov, Henning Paul-Julius Stahlberg

Protein translocation by the bacterial type VI secretion system (T6SS) is driven by a rapid contraction of a sheath assembled around a tube with associated effectors. Here, we show that TssA-like or TagA-like proteins with a conserved N-terminal domain and varying C-terminal domains can be grouped into at least three distinct classes based on their role in sheath assembly. The proteins of the first class increase speed and frequency of sheath assembly and form a stable dodecamer at the distal end of a polymerizing sheath. The proteins of the second class localize to the cell membrane and block sheath polymerization upon extension across the cell. This prevents excessive sheath polymerization and bending, which may result in sheath destabilization and detachment from its membrane anchor and thus result in failed secretion. The third class of these proteins localizes to the baseplate and is required for initiation of sheath assembly. Our work shows that while various proteins share a conserved N-terminal domain, their roles in T6SS biogenesis are fundamentally different.

WILEY2019

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Cellular stress response

Cellular stress response is the wide range of molecular changes that cells undergo in response to environmental stressors, including extremes of temperature, exposure to toxins, and mechanical damage.