Xenophagy and LC3-associated phagocytosis (LAP) Flashcards
Name the two forms of autophagy.
The two forms of autophagy are the canonical xenophagy and the non-canonical LC3-associated phagocytosis (LAP).
What machinery is required for LAP?
The LC3-lipidation machinery, the Atg5-12-16L1 complex, the protein Rubicon, and the generation of reactive oxygen species (ROS) by the NADPH oxidase.
What machinery is required for xenophagy?
The ULK1 complex, the Atg5-12-16L1 complex, and LC3-II.
How does Mycobacterium tuberculosis damage the phagosomal membrane and enter the cytosol?
By using the coordinated action of the ESX-1 Type 7 secretion system (T7SS).
What is the function of ATG7 and ATG14?
ATG14 has a function in regulating fusion of autophagosomes containing Mycobacterium tuberculosis with lysosomes, and also has a function in the endosomal pathway that is autophagy-independent. Both ATG7 and ATG14 control the replication of cytosolic bacteria through either recapture of bacteria from the cytosol or sealing of damaged phagosomes by autophagosomes as reported for Salmonella. ATG7 and ATG14 are required to control Mtb infection.
What does autophagy entail?
Autophagy, which can be called the “housekeeping system”, entails the sequestration of cargo in a double membrane vesicle.
What is xenophagy? How does it function?
Xenophagy is the autophagy of microbial invaders. Xenophagy functions in the direct elimination of invaders, activation of immune responses, inflammasome control, and antigen presentation.
Give the pathway of xenophagy.
In xenophagy, phagocytic cells engulf a pathogen, and the pathogen is sequestered in a double membrane vesicle named the autophagosome. Subsequently, the autophagosome is fused with a lysosome containing antimicrobial toxins, and the pathogen is degraded in this autolysosome. In xenophagy with viral pathogens, a virus is engulfed by a phagocytic cell and viral nucleic acids are then sequestered in an autophagosome. The autophagosome containing viral nucleic acid is then turned into an endosome and the viral nucleic acid can be recognised to induce expression of type 1 interferons (interferon-a and interferon-B).
Which factors induce autophagy?
Microbial invaders, low energy, and nutrient limitation.
Is autophagy always host-protective?
No, autophagy can be host-protective by delivering pathogens to lysosomal degradation. However, several pathogens subvert or hijack autophagy to facilitate replication and spreading (e.g. the poliovirus, a nonlytic virus which spreads by autophagy-mediated secretion pathways).
Give the pathway of autophagosome maturation.
In autophagy, due to an infection or due to low energy or nutrient limitation, a double membrane isolation membrane is formed, which recruits the protein LC3. LC3 can be present in two forms: in the cytosol it is called LC3-I, and when it is lipidated and is able to conjugate to the autophagosome membrane, it is called LC3-II. After the double membrane isolation membrane is formed, the isolation membrane elongates, LC3-II is recruited to the membrane, and cargo (pathogens, mitochondria, etc.) is recruited. This state of the isolation membrane is called the phagophore. After completion of the phagophore, it is called an autophagosome and it can fuse with a lysosome to form an autolysosome, which degrades the cargo inside.
How do selective autophagy receptors (SLRs) function in xenophagy.
Salmonella can escape phagocytosis and end up in the cytosol, after which it is recognised by the ubiquitin machinery, after which the bacterium can be sequestered in an autophagosome and lysed. SLRs, like Atg8, recognise ubiquitin and/or galectins on bacteria or damaged phagosomes and target them to LC3-II. SLRs also deliver neo-antimicrobial peptides derived from ubiquitinated proteins. These ubiquitinated proteins are often useful precursors for new antimicrobial peptides. These neo-antimicrobial peptides and the ubiquitinated pathogen end up in the same autophagosome, where the antimicrobial peptides can degrade the pathogen.
Give the pathway of LC3-associated phagocytosis (LAP).
With LC3-associated phagocytosis (LAP), the cell membrane engulfs a pathogen in just a single membrane (unlike the double membrane vesicles of xenophagy). This single membrane vesicle also recruits the LC3 protein, but only after undergoing a respiratory burst of reactive oxygen species (ROS). Then, this single membrane isolation vesicle is called a LAPosome. The protein Rubicon induces LC3-associated phagocytosis and inhibits xenophagy. Afterwards, a LAPosome can fuse with a lysosome to form a phagolysosome.
Why is it important that both xenophagy and LAP can occur in cells?
Both pathways of xenophagy and LAP are very important, because, for example, xenophagy is protective against Staphylococcus aureus infection, but LAP provides a replication niche for Staphylococcus aureus in neutrophils. So, enhancing autophagy might be useful for infections of Salmonella, but are detrimental for infections of Staphylococcus aureus, where LAP provides a replication niche and thus LAP should be inhibited to provide host resistance.
