Autophagy in Disease - Protein Misfolding and Cellular Stress in Disease and Aging - page 77

been the subject of recent comprehensive reviews and we direct
readers interested in the full details of specific aspects of autophagy
to the relevant sources ( 1-14 ).

2. Autophagy:
Basic Principles

2.1. Major Types
of Autophagy
in Mammalian Cells

In mammalian cells, three forms of autophagic process have been
described: macroautophagy, microautophagy, and chaperone-
mediated autophagy (CMA). These differ morphologically and
mechanistically, and presumably crosstalk between them can
occur depending on the particular circumstances, although the
details remain to be elucidated. When reports refer to autophagy,
unless specified otherwise, it is macroautophagy that is being
considered.

Macroautophagy involves the sequestration of cytoplasmic con-
stituents including macromolecular structures (e.g., ribosomes),
long-lived proteins, protein aggregates, organelles (e.g., mito-
chondria, peroxisomes, endoplasmic reticulum (ER)), and even
pathogens into double-membrane vesicles called autophagosomes
(APs). These APs fuse with lysosomal membranes liberating
single-membrane vesicles, into the lumen of the lysosome where
they are degraded by the resident hydrolases ( 11, 14 ) (Fig. 1 ).
The origin of AP membranes remains a matter of debate, with
some support for the suggestion that they originate from the
ribosome-free ER ( 11, 15 ). The mechanistic details of AP for-
mation and degradation have been best studied in the yeast,
Saccharomyces cerevisiae , facilitated by its genetic malleability and
the isolation of mutants defective in autophagy and related pro-
cesses ( 16 ); 31 ATG genes (AuTophaGy) have been described.
The steps in AP formation and degradation are: (1) induction,
(2) AP nucleation, (3) cargo recognition, (4) AP completion,
(5) Atg protein cycling, (6) AP fusion with lysosomes, (7) break-
down, and (8) recycling ( 17 ). The process of macroautophagy in
higher eukaryotes is essentially the same as that in yeast. To date,
human orthologs of some 17 yeast ATG genes have been identi-
fied ( 4, 18 ) (Fig. 1 , as indicated in brackets). For a more detailed
description of the molecular mechanism of macroautophagy, the
reader is referred to specialised reviews ( 4, 17-20 ).
Extracellular (nutrient starvation, hormone, or pharmaco-
logic treatment) as well as intracellular stimuli (accumulation of
misfolded proteins and protein aggregates, invasion by patho-
gens) are able to modulate the autophagic response. As autophagy
occurs at a basal, constitutive level under normal conditions, there
must be mechanisms by which extracellular and/or intracellular
signals are transmitted to the regulatory factors to promote or

2.1.1. Macroautophagy