User:Kinkreet/Autophagy in Immunity and Inflammation

Autophagy is the catabolic process by which a cell breaks down its own cellular components using lysosomal degradation. Small peptides and proteins can be degraded using the proteasome, but larger structures such as organelles and large protein aggregates, need to be transported to a lysosome to be degraded.

Autophagy is employed during a stress response, where nutrients are scarce, and there are evidence which shows the autophagy pathway interacting with most stress response pathways. One example is during starvation, the target of rapamycin (TOR), a nutrient-responsive kinase, is inhibited, thereby inducing autophagy. Autophagy is also employed to counter invading and phagocytosed pathogens, as it is the only mechanism capable of degrading such large structures; recently it has also been found to be involved in the control of immunity and inflammation. The immune and inflammation response are controlled (both inductive and suppressive) partly by the autophagy pathway, but the autophagy pathway is also partly controlled by the immune and inflammation response - the relationship is reciprocal. Mutants for the genes involved in autophagy displayed increased susceptibility to infection caused by intracellular pathogens.

There are three types of autophagy: Macroautophagy, chaperone-mediated autophagy, and microautophagy. Macroautophagy is usually the type referred to when autophagy is mentioned.

Mechanism
The process of macroautophagy begins with a double-layered 'isolation membrane' surrounding a portion of the cytoplasm (0.5-1μm in diameter). As it surrounds the area, the membrane also grows larger, and cargo are recruited to the inner face of the membrane. The isolation membrane would eventually close up and forma a double-membraned autophagosome. The autophagosome is then transported to a lysosome and fuse to form a autolysosome, in which the lysosomal enzymes would be used to degrade the cargo.

The autophagosome can also be merged with endosomes, multi-vesicular bodies and MHCII-loading compartments, which allows the contents of the autophagosome, some of which may be antigens from the intracellular pathogen, to be displayed on the cell surface. In MHCII positive cells (namely activated antigen presenting cells), the formation and fusion of autophagosomes with MHCII-loading compartments are constitutive.

As autophagy requires many lysosomes to fuse with autophagosomes, the homeostasis of the number of lysosomes in the cell must be maintained. As mentioned previously, during starvation, TOR is inhibited and this induces autophagy; but in prolonged starvation, TOR is shown to be reactivated and this attenuates autophagy. The autolysosome forms tubules that extrude from the walls, and these mature to reform lysosomes, and thus the homeostasis is maintained.

To be incorporated
Yolk proteins are degraded while zygotic proteins are synthesised during embryonic development in animals, this leads to intracellular remodelling and cellular differentiation.

A screen of S. cerevisiae showed that there are 31 autophagy related genes (ATG genes)

In S. cerevisiae, autophagy requires two highly conserved ubiquitin-like conjugation systems. The first system involves the ubiquitin-like protein Atg12 being activated by Atg7 (an E1 enzyme), transferred to Atg10 (an E2 enzyme) and conjugated to Atg5. The second system aims to lipidize the C-terminal of Atg8 (an unbiquitin-like protein) so it can be attached to phosphatidylethanolamine (PE). First Atg8 is cleaved by Atg4, then activated by Atg7 and transported to Atg3 (another E2 enzyme) which lipidize Atg8.

Atg8 remains with the autophagosome and is degraded in the lysosome, therefore, tracking Atg8 is a good way for tracking autophagosomes in S. cerevisiae.

"Humans have approximately seven Atg8 homologs, including microtubule-associated protein 1 light chain 3 (LC3) isoforms A, B and C, gamma-aminobutyric acid A receptor-associated protein (GABARAP) and its L3 isoform, Golgi-associated ATPase enhancer of 16 kDa (GATE-16) and Atg8-like protein (ATG8L), and the best studied of these is LC3. LC3 is conjugated to PE in response to starvation conditions or chemical treatments that upregulate autophagy. GABARAP shows many similarities with LC3 but its conjugation is only mildly affected by starvation, and under certain conditions conjugation may be activated independent of mTOR inactivation. GATE-16 is proposed to be involved in intra-Golgi transport and postmitotic Golgi reassembly. ATG8L is the least studied homolog, and the function of GATE-16 and ATG8L in autophagy is not well understood."