AUTOPHAGY: A CORE CELLULAR PROCESS WITH EMERGING LINKS TO
Running Title: Role of Autophagy in Lung Disease
Jeffrey A. Haspel1, 2, and Augustine M. K. Choi1,*
1 Division of Pulmonary and Critical Care Medicine, Department of Medicine; Brigham and
Women’s Hospital; 75 Francis Street; Boston, MA, 02115; USA.
2 Pulmonary and Critical Care Medicine Section, VA Boston Healthcare System, Boston, MA, USA.
Author Contributions: J.A.H and A.M.K.C co-wrote this review article.
Descriptor Number: 8.2 (Airway Pathology and Structure)
Funding Support: NIH T32 HL007633 and R03 HL097005.
Narrative Word Count: 4,981
Scientific Knowledge on the Subject: a growing body of literature indicates that autophagy is
linked to the pathogenesis of common pulmonary disorders.
What this Study Adds to the Field: this review provides an introduction to the field of autophagy
for clinical and research Pulmonologists previously unfamiliar with this topic. It also reviews
current evidence linking regulation of autophagy to common pulmonary diseases.
This article has an online data supplement, which is accessible from this issue's table of content
online at www.atsjournals.org
Page 1 of 51
AJRCCM Articles in Press. Published on August 11, 2011 as doi:10.1164/rccm.201106-0966CI
Copyright (C) 2011 by the American Thoracic Society.
Autophagy is a highly conserved homeostatic pathway by which cells transport damaged
proteins and organelles to lysosomes for degradation. Dysregulation of autophagy
contributes to the pathogenesis of clinically important disorders in a variety of organ
systems but, until recently, little was known about its relationship to diseases of the
lung. However, there is now growing evidence at the basic research level that
autophagy is linked to the pathogenesis of important pulmonary disorders such as
COPD, cystic fibrosis and tuberculosis. In this review, we provide an introduction to the
field of autophagy research geared to clinical and research Pulmonologists. We focus on
the best studied autophagic mechanism, macroautophagy, and summarize recent
studies that link the regulation of this pathway to pulmonary disease. Finally, we offer
our perspective on how a better understanding of macroautophagy might be utilized for
designing novel therapies for pulmonary disorders.
Abstract Word Count: 143
Keywords: autophagy, macroautophagy, lung, disease, COPD.
Page 2 of 51
At the cellular level, homeostasis is maintained by a series of deeply conserved
pathways of which “autophagy” is one central pillar. Autophagy refers to a collection of
catabolic pathways that transport components of the cytoplasm to lysosomes for
degradation (1). In addition to proteins, autophagy can target both carbohydrates (2, 3)
and lipids (4) for digestion as well as entire organelles, such as mitochondria and
peroxisomes (5-7). The products of digestion, such as free amino acids, are recycled
back to the cytoplasm for use in various biosynthetic pathways (8). Autophagy
contributes to cellular homeostasis via three basic mechanisms. First, autophagy
provides an alternative source of metabolic fuel (9). Second, autophagy removes
damaged cellular components, such as dysfunctional mitochondria and aggregated
proteins that would otherwise be toxic to the cell (7, 10, 11). Finally, autophagy is
entwined at the signal transduction level with the apoptotic pathway and impacts the
decision of a cell to undergo programmed cell death (12, 13). To study autophagy is to
study an aspect of the core operating system that enables eukaryotic cells to function.
Which begs the question: what does autophagy have to do with patients suffering from
pulmonary disease? Interestingly, the answer may be “quite a lot”. The purpose of this
review is twofold: to provide a basic introduction to the rapidly expanding field of
autophagy research with an emphasis on the most studied autophagic pathway
(macroautophagy), and also to review recent studies that link autophagic regulation to
Page 3 of 51
HOW DOES AUTOPHAGY WORK?
At present there are three known mechanisms by which autophagy can occur (Fig. 1).
The first mechanism is called Chaperone Mediated Autophagy (CMA) and was originally
described in lung fibroblasts (Fig. 1A) (14). This mechanism involves the direct
translocation of proteins across the lysosomal membrane via a complex that includes
Hsc70 and the lysosome transmembrane protein Lamp2A (15, 16). CMA is difficult to
monitor in vivo and at this point we don’t have any information about whether this
pathway is affected in pulmonary disease. However CMA plays an important role in the
pathogenesis of neurodegeneration and aging (17, 18), and is still an evolving field of
biomedical research. The second autophagic pathway is called microautophagy and
involves the direct invagination of cytosolic material into late endosomes or into
multivesicular bodies, which subsequently either degrade the material on site or deliver
the material to lysosomes for degradation (19). Until very recently nothing was known
about microautophagy at the molecular level and the existence of this process was only
suspected in mammalian tissues on the basis of electron micrographs. However it was
recently shown that microautophagy also employs Hsc-70 but, unlike CMA, it targets
proteins to late endosomal membranes through electrostatic interactions between this
chaperone and the lipid phospatidylserine, rather than by binding to LAMP2A (Fig. 1B)
(20). Microautophagy is similarly difficult to measure in vivo and so little is understood
Page 4 of 51
about its physiological significance at this point, although this may change as the
molecular mechanism is better defined.
The final pathway, macroautophagy (21), receives the most attention in the literature
and its contribution to human disease is the best explored of the three pathways. In
fact, macroautophagy so much better studied that it is often referred to in many papers
as simply “autophagy”, even though it is only one of the pathways involved in lysosome-
dependent degradation. This is in large part because macroautophagy can be visualized
at both the light microscopic level (using fluorescent fusion proteins), and at the EM
level making it relatively easy to detect (22). In macroautophagy, a vesicular membrane
is constructed around a volume of cytoplasm that is intended for degradation (Fig. 1C).
This novel structure, called an autophagosome, is distinct from other vesicles on
electron micrographs because it contains a double-unit limiting membrane (21).
Autophagosomes then deliver their cargo for degradation by fusing with late
endosomes and lysosomes, gradually losing their distinctive membrane structure (23).
The products of digestion, such as free amino acids, are recycled back to the cytoplasm
via lysosomal permeases (8). Of the three known autophagic pathways,
macroautophagy is notable for its ability to process large intracellular structures such as
organelles (5, 6), invasive bacteria in the cytoplasm (24, 25), and large protein
aggregates (10). Macroautophagy is sensitive to nutrient availability (19, 26), and is
altered in a variety of non-pulmonary diseases, such as neurodegeneration (27),
myopathy (28, 29), and cancer (30). All of the current literature about the role of
Page 5 of 51