Group A Streptococcus modulates RAB1- and PIK3C3 complex-dependent autophagy

Area of Science:

• Cellular microbiology
• Immunology
• Molecular biology

Background:

• Autophagy is a cellular defense mechanism against bacterial pathogens.
• Bacterial pathogens, like Group A Streptococcus (GAS), have evolved strategies to evade or manipulate autophagy for survival.
• Canonical autophagy initiation involves the PIK3C3 complex, but GAS infection has been shown to involve PIK3C3-independent pathways.

Purpose of the Study:

• To investigate the interplay between GAS infection and host cell autophagy.
• To elucidate the role of the GAS effector NAD-glycohydrolase (Nga) in modulating autophagy.
• To identify distinct autophagy pathways involved in targeting GAS infection.

Main Methods:

• Analysis of PIK3C3-dependent and -independent autophagy during GAS infection.
• Investigating the function of GAS effector Nga in modulating autophagy.
• Utilizing genetic and biochemical approaches to study autophagy regulators like ATG14 and RAB GTPases.
• Monitoring ATG14 recruitment to GAS and its relation to PIK3C3 complexes.

Main Results:

• GAS infection induces both PIK3C3-dependent and -independent autophagy.
• The GAS effector Nga selectively modulates PIK3C3-dependent autophagy.
• Nga suppresses PIK3C3-dependent autophagosome formation targeting GAS during early infection, facilitating intracellular proliferation.
• Nga-sensitive autophagy involves the ATG14-containing PIK3C3 complex and RAB1, while Nga-insensitive autophagy utilizes RAB9A/RAB17.
• GAS infection impairs ATG14 recruitment to bacteria, indicating Nga's role in inhibiting PIK3C3 complex assembly at autophagosome formation sites.

Conclusions:

• GAS employs a sophisticated mechanism involving Nga to subvert canonical autophagy.
• Distinct autophagy pathways, regulated by different components like ATG14 and RAB GTPases, are involved in targeting GAS.
• This study uncovers a novel GAS-host interaction and highlights the existence of multiple, differentially regulated autophagy pathways against bacterial pathogens.