Molecular Mechanism and Regulation of Autophagy in Mammalian

Cells
Julio Francisco
Florida Institute of Technology, Dept. of Biological Science

Autophagy is a catabolic process in which cellular components are engulfed by a

specialized vesicles called autophagosomes and delivered to lysosome for degradation and

recycling (Eskelinen & Saftig, 2009).

Autophagy was initially discovered more than 40 years ago when Clark and Novikoff

observed a dense bodies within the mitochondrial membrane containing lysosomal enzymes

(Yang & Klionsky, 2010). Ashford and Porter later observed membrane-bound vesicle

containing semi-digested mitochondria and endoplasmic reticulum. These membrane-containing

digested material would be later be known as autophagosomes.

Today the field of autophagy has progressed. We now know that autophagy is

conserved catabolic mechanism in eukaryotic cells. Autophagy plays a role in degrading cellular

materials such as long-lived proteins, damaged organelles, and invasive pathogens (He &

Klionsky, 2009; Stolz, Ernst, & Dikic, 2014). In addition, autophagy can degrade aggregated

protein known to cause neurodegenerative diseases. For example, autophagy can break down

aggregated proteins such as tau (known to cause of dementia), -synuclein (Parkinsons

disease), and mutant huntingtin (Huntingtons disease) (Bento et. al., 2016). Additionally,

autophagic activity typically increases during intra- and extracellular stress such as starvation,

ER (endoplasmic reticulum) stress, growth factor deprivation, and pathogenic infection (He &

Klionsky, 2009).

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 Defectiveness of autophagy can lead to progressive diseases such as cancers,

infectious diseases, and aging (He & Klionsky, 2009). Also, autophagy plays a role in metabolic

disease, cardiac disease, stroke, and hematopoiesis.

Overall, autophagy allows orderly degradation and recycling of cellular components, and

defectiveness of this autophagic machinery can lead to various diseases. (He & Klionsky, 2009).

In this literature review, a description of the type of autophagy will be discussed. In

addition, this paper will provide both a general overview and an in-depth report on the regulation

and molecular mechanism of autophagy in mammalian cells. Lastly, this review will address

events in which autophagic activities is up-or downregulated.

Type of Autophagy

There are four types of autophagy: macroautophagy, microautophagy,

chaperone-mediated autophagy, and non-canonical autophagy (Deretic, Saitoh & Akira, 2013).

In macroautophagy, cellular materials are sequestered within a membrane-bound intracellular

vacuole called autophagosome, which fuses with lysosome for degradation of autophagosomal

contents (Eskelinen & Saftig, 2009). In microautophagy, a cytoplasmic cargo is directly engulfed

by nearby lysosome (Eskelinen & Saftig, 2009). In chaperone-mediated autophagy, cytoplasmic

proteins containing KFERQ motif are recognized and transported by Hsc70 (heat shock cognate

71 kDa protein) directly to the lysosome lumen through a glycoprotein called Lamp-2a

(Lysosome-associated membrane protein 2) for degradation (Oh & Lee, 2013). Non-canonical

autophagy is an alternative form of macroautophagy (Codogno, Mehrpour & Proikas-Cezanne,

2012). This pathway is still being research.

These autophagic machineries serve two physiological purposes: constitute (basal) or

adaptive. Constitute autophagy is the removal of damaged or senescent (aged) organelles and,

as a result, it ensure the maintenance of basal energy balance (Deretic, Saitoh & Akira, 2013).

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On the other hand, adaptive autophagy is the movement nutrient in order to meet nutrient

requirements in a deficiency environment (Deretic, Saitoh & Akira, 2013).

All and all, autophagy is divided into macroautophagy, microautophagy,

chaperone-mediated autophagy, and non-canonical autophagy. It also can be classified as

constitute or adaptive. As of this point, macroautophagy will be the focus of this paper and,

hereafter refer macroautophagy to autophagy.

General Overview of autophagy

Autophagy is highly selective and degrades cellular materials to be recycled into building

blocks or to use as an energy source. Autophagic process is divided into six major steps: (1)

initiation of autophagy, (2) vesicle formation, (3) cargo selection, (4) phagophore expansion, (5)

autophagosome-vacuole fusion and degradation, and (6) termination (He & Klionsky, 2009).

The first step (initiation of autophagy) occurs under cellular stresssuch as nutrient

starvation, reduced growth signals, or pathogenic infectioncausing a cascade of cellular

events occurs to initiate vesicle formation (see Figure 1; He & Klionsky, 2009). In the next step

(cargo selection), damaged organelles, aggregated proteins, or even the pathogen itself are

tagged and recognized by specialized autophagy receptors. These receptors deliver the tagged

components to the forming vesicle. The vesicular membrane elongates and close, developing

into a mature autophagosome. The autophagosome is docked and fused to a lysosome. The

lysosomal enzymes degrades targeted material which will be recycled within the cells.

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Image from http://www.wormbook.org/chapters/www_autophagy/autophagyfig1leg.jpg

Figure 1. Formation of autolysosomes. An autophagic membrane is formed under cellular

stress. The first membrane formed is a double-layered crescent shape membrane called
phagophore (sometime called isolation membrane). Autophagic receptor deliver target cellular
components to the growing membrane. The membrane is matured into an autophagosome
containing targeted materials. The autophagosome is then docked and fused with a lysosome,
forming an autolysosomes. Within the autolysosomes, the lumen is acidified, and lysosomal
hydrolases degrade the autophagosomal contents.

Initiation of Autophagy

The best known regulatory factors of autophagy in mammalian cells are mechanistics

target of rapamycin complex 1 (mTORC1) and 5' AMP-activated protein kinase (AMPK) (Sica et.

al., 2015).

mTORC1 is a serine/threonine protein kinase that not only regulates autophagy but also

regulates transcription, metabolism, and transcription in response to nutrients and growth factor

deprivation (Jung et. al., 2010). Normally, mTORC1 inhibits autophagy by phosphorylate and

inactivate both ULK 1 (UNC-51-like kinases 1) and ATG13 (Autophagy Related 13) (Sica et. al.,

2015). On the other, when mTORC1 is inactivated during cellular stress, both ULK 1 and

ATG13 becomes active, causing autophagy occurs.

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 mTORC1 activity can be regulated by the amount of nutrient available in the cell such

as amino acid and glucose (Jung et. al., 2010). For instance, glucose is involved in the pathway

which maintains cellular energy (Sica et. al., 2015). During glucose starvation, the ratio of ATP

and AMP is reduced. As a result, ADP, AMP, and cyclic AMP (cAMP) are accumulated (Sica et.

al., 2015). Such accumulation activates AMPK (Sica et. al., 2015). AMPK then phosphorylates

and activates tuberous sclerosis 2 (TSC2) (Sica et. al., 2015). TSC2 inhibits mTORC1 (Sica et.

al., 2015). AMPK also activates ULK1 and Beclin 1 proteins. Beclin 1 activates VPS34 complex.

VSP34 phosphates PtdIns3P, leading to autophagy (see figure 2). Interestingly, nutrient

starvation can be induced by microorganism in which the pathogen compete against the host for

nutrient (Deretic, Saitoh & Akira, 2013). Microorganism-induced nutrient deficiency causes

autophagy to occur (Deretic, Saitoh & Akira, 2013). This is due to the fact that there is a

shortage of amino acid from the microorganism competition, causing the cells to think that it is

starving and leads to the activation of autophagy process (Deretic, Saitoh & Akira, 2013)

Another glucose sensing pathway involves glyceraldehyde-3-phosphate dehydrogenase

(GAPDH) (see figure 3). In this pathway, AMPK phosphorylates and activates GAPDH (Chang

et. al., 2015). GAPDH is translocated into the nucleus where it interactive with sirt1 (Chang et.

al., 2015). This causes DBC1 to dissociate, allow sirt1 to be activated and autophagy to occur

(Chang et. al., 2015).

Furthermore, autophagy is not exclusively triggered during nutrient deprivation.

Autophagy can be triggered due to a reduction in growth factor signalling (Jung et. al., 2010).

One of the key growth factor signaling is insulin/ insulin-like growth factor (IGF-1)-PI3K

(phosphoinositide 3-kinase class-I)-Akt pathway. The insulin/IGF-1-PI3K-Akt pathway is initiated

with the binding of an insulin or growth factor to an insulin receptor (Ravikumar et. al., 2010).

This trigger a cascade of event as shown in Figure 4, leading to autophagy.

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 Lastly, autophagy can be induced during cellular stresses such as hypoxia (low oxygen).

In a hypoxic environment, REDD (REgulated in Development and DNA damage)-1 and-2 is

triggered (Jung et. al., 2010). REDD1 negatively regulates mTORC1, leading to autophagic

activity; however, the mechanism is unknown (Jung et. al., 2010).

Overall, autophagy is induced by inhibition of mTORC1 complex during nutrient

starvation. Other ways of triggering autophagy is decrease in growth factor signalling, ER

stress, and hypoxia condition. There are other regulation mechanisms; however, discussion of

all circumstances is beyond the scope of this paper.

Image from Kim, J., Kundu, M., Viollet, B., & Guan, K.-L. (2011). AMPK and mTOR regulate autophagy
through direct phosphorylation of Ulk1. Nature Cell Biology, 13(2), 132141.

Figure 2. AMPK and mTOR regulate autophagy. In a high glucose environment, there is a
high ratio of ATP to AMP. As a result, mTOR complex suppresses autophagy by inhibiting
ULK1, Atg13, and FIP2000 (focal adhesion kinase family interacting protein of 200kDa; Kim et
al. , 2011). However, during glucose deprivation, there is a reduced ratio of ATP to AMP,
leading to the accumulation of AMP, ADP, and cyclic AMP (cAMP; Sica et. al., 2015). This
triggers the activation of AMPK. AMPK phosphorylates and activates mTOR complex inhibitor,

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tuberous sclerosis complex 2 (TSC2; Sica et. al., 2015). TSC2 inhibits mTOR complex (Sica et.
al., 2015). ULK is activated which ULK1 activates Atg13. Atg13 activates FIP200, allowing for
autophagy to occur (Sica et. al., 2015).

Image from Chang, C., Su, H., Zhang, D., Wang, Y., Shen, Q., Liu, B., Huang, R., Zhou, T., Peng, C.,
Wong, C., Shen, H., Lippincott-Schwartz, J. & Liu, W. (2015). AMPK-Dependent Phosphorylation of
GAPDH Triggers Sirt1 Activation and Is Necessary for Autophagy upon Glucose Starvation. Molecular
cell, 60 (6), 930-40.

Figure 3. GAPDH-dependent Pathway. In the absence of glucose but in the presence of

amino acid, AMPK phosphorylate GAPDH at the Ser122 position (Chang et. al., 2015). GAPDH
is transported into the nucleus (Chang et. al., 2015). GAPDH interacts with Sirt1 (Chang et. al.,
2015). This cause the Sirt1 inhibitor, DBC1, to be displaced, allowing sirt1 to activate and
autophagy to occur (Chang et. al., 2015).

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Image from Ravikumar, B., Sarkar, S., Davies, J. E., Futter, M., Garcia-Arencibia, M., Green-Thompson,
Z. W., . . . Rubinsztein, D. C. (2010). Regulation of mammalian autophagy in physiology and
pathophysiology. Physiological Reviews, 90(4), 1383-1435.

Figure 4. Insulin/ insulin-like growth factor (IGF-1) PI3K (Phosphoinositide 3-kinase-Akt

pathway. An insulin (or growth factor) binds to the insulin receptor (Ravikumar et. al., 2010).
PI3K is activated and converts PIP2 to PIP3 (Ravikumar et. al., 2010). This cause the
recruitment of phosphoinositide-dependent kinase 1 (PDK1) and Akt (Ravikumar et. al., 2010).
Akt is phosphorylated and activated (Ravikumar et. al., 2010). Next, Akt phosphorylates and
activates TSC 1/2, leading to activation of Rheb (Ras homology enriched in brain; Ravikumar et.
al., 2010). mTORC1 suppresses autophagy by inhibiting ULK1, Atg13, and FIP2000 (Ravikumar
et. al., 2010). However, when there is a reduction in insulin growth factor signalling, mTORC1 is
inhibited, allowing ULK1 to phosphorylate Atg13. Atg13 then phosphorylate FIP200, which
allows autophagy to occur (Jung et. al., 2010).

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 Vesicle formation

In 1988, Seglen used radioactive probe to study early and intermediate steps of

autophagy (Yang & Klionsky, 2010). He identified a double-layered crescent shape membrane

what is now called phagophore (also known as isolation membrane) (Yang & Klionsky, 2010).

It is now known that the formation of phagophore is initial step in autophagy. However, it

is still unclear where exactly phagophore formation originated (Longatti & Tooze, 2009). Recent

studies showed that the ER is a possible site for membrane source (Shibutani & Yoshimori,

2014). Other possible sources of membrane include the mitochondria, the ER-Golgi

intermediate compartment (ERGIC), the Golgi appartus, recycling endosome, and plasma

membrane (Shibutani & Yoshimori, 2014).

Furthermore, it was shown that ULK1/2 complex initiates the formation of phagophore.

As we seen before, mTORC1 inhibits ULK1 and therefore inhibits the formation of phagophore.

However, during an intra- or extracellular stress, mTORC1 is blocked by TSC2, activating ULK1.

Once ULK1 is activated, this would lead to a cascade of events. First, ULK1 will forms a

complex with ULK2. Next, ULK1/2 complex bind to membrane and recruit Vps34 (vacuolar

protein sorting 34) complex to the phagophore (Brento et. al., 2016). Then, Vps34 complex

phosphorylates PIs (phosphoinositides), leading to the production of

phosphatidylinositol-3-phosphate (PI3P) (Weidberg, Shvets, & Elazar, 2011). PI3P recruits

effector molecules to the phagophore (Weidberg, Shvets, & Elazar, 2011). The PI3P effectors

includes WIPI (WD repeat protein interacting with phospoinositides) family and DFCP1 (double

FYVE domain-containing protein) (Weidberg, Shvets, & Elazar, 2011). These effector molecules

can recruit other proteins. For example, WIPI 2 can recruit Atg16L along with other proteins

(Brento et. al., 2016). Atg16L usually forms a complex with Atg12 and Atg5 (Brento et. al.,

2016). Also, Atg16L recruits LC3 II (microtubule-associated protein 1 light chain 3) to the

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phagophore (Weidberg, Shvets, & Elazar, 2011). Both the Atg5-12-16L complex and

LC3-lipidation system were shown to control the elongation and closure of phagophore (Longatti

& Tooze, 2009). The membrane eventual close forming an autophagosome which would later

fuse with a lysosome to degrade the autophagosomal content.

Brento, C. Renna, M., Ghislat, G., Puri, C., Ashkenazi, A., Vicinanza, M. Menzie, F. & Rubinsztein, D.
(2016). Mammalian autophagy: How does it work? Annual Review of Biochemistry,
doi:10.1146/annurev-biochem-060815-014556.

Figure 5. Biogenesis of mammalian autophagosome. ULK1/ 2 complex initiates the the

formation of phagophore membrane (Weidberg, Shvets, & Elazar, 2011). Next, Vps34 complex
is recruited to the phagophore and phosphorylates PI, leading to the production of PI3P
(Weidberg, Shvets, & Elazar, 2011). PI3P recruits effector proteins, such as WIPI1/WIPI2 and

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DFCP1 (double FYVE domain-containing protein) (Weidberg, Shvets, & Elazar, 2011).
Atg5-12-16L complex is recruited to the phagophore (Weidberg, Shvets, & Elazar, 2011).
Atg16L recruits LC3 II to the phagophore membrane (Weidberg, Shvets, & Elazar, 2011).
Atg5-12-16L complex and LC3 II are required for the elongation and closure of phagophore
(Weidberg, Shvets, & Elazar, 2011). Eventually, a mature autophagosome is formed (Weidberg,
Shvets, & Elazar, 2011).

Cargo selection
Before a mature autophagosome is formed, dysfunctional organelles, aggregate-protein

and infectious agent are recruited to the autophagosomal membrane by autophagy receptors

(Brento et. al., 2016). In particular, these receptors bind to the cellular components, often

through the ubiquitinated site, and attach them to the autophagic membrane to be later digested

(Brento et. al., 2016). Sequestosome-1, optineurin, NDR1, p62, NDP52 (nuclear dot protein 52

kDa), and ALFY (autophagy-linked FYVE protein) are examples of autophagy receptors and

adaptor proteins (Kim & Lee,2014; Brento et. al., 2016).

Phagophore Expansion

It is unclear how the autophagic membrane extend. Longatti and Tooze (2009) proposed

four models for phagophore expansion (see Figure 6). In model 1 (called the lipid delivery/ de

novo synthesis model), the phagophore is extended by the de novo delivery of lipids, lipid

droplets, or micelles (Longatti & Tooze, 2009). These lipids are delivered by spontaneous

exchange and insertion, or through lipid transfer proteins (Longatti & Tooze, 2009). A third

alternative is that phagophore near the smooth ER could be provide fatty acids for de novo

autophagosomal membrane formation (Longatti & Tooze, 2009).

In the second model (also known as the vesicular transport model), membrane is

delivered via vesicular transport to the growing phagophore (Longatti & Tooze, 2009). In Model

3 (cisternal assembly model), either autophagic vesicles or discrete phagophore fuses with the

growing phagophore (Longatti & Tooze, 2009). The fourth model (also known as the membrane

remodelling extension) proposed that a pre-existing membrane gradually expands by the

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connecting to specific membrane protein and lipid to the pre-existing phagophore (Longatti &

Tooze, 2009). The extended membrane would curves and close up due to the membrane

composition (Longatti & Tooze, 2009).

The first three models is based on established mechanism of lipid movement and

vesicular trafficking (Longatti & Tooze, 2009). However the last model is based on Longattis

and Toozes speculation and on the idea that phagophore is derived from the ER. This field is

still unknown and research are continue to investigate how the membrane are extend.

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Image from Longatti, A. & Tooze, S. (2009). Vesicular trafficking and autophagosome formation. Cell
Death and Differentiation, 16, 956-65.

Figure 6. Four Models for Phagophore Expansion. (1) Model 1 (lipid delivery/ de novo
synthesis model) is de novo lipid delivery to sealed bilayer membrane or opened bilayer
membrane with a capped protein (Longatti & Tooze, 2009). (2) In Model 2 (vesicular transport
model), membrane is delivered via vesicular transport to the growing phagophore (Longatti &
Tooze, 2009). (3) In Model 3 (cisternal assembly model), either autophagic vesicles or discrete
phagophore fuses with the growing phagophore (Longatti & Tooze, 2009). (4) In Model 4
(membrane remodelling/ extension model), pre-existing membrane extends by retention of
resident proteins and lipids. Then, this membrane would curve and close due to the composition
of the membrane.

Autophagosome-Lysosome Fusion and Degradation

When phagophore transforms to a mature autophagosome, RABs (members of the Ras

superfamily of monomeric G protein) recruits motor proteins such as kinesin and dynein (Brento

et. al., 2016). Both of these motor proteins are involved in the movement of autophagosome to

the lysosome (Brento et. al., 2016) in which these motor proteins can transport autophagosomal

cargoes along microtubules and actin filaments to the lysosome (Brento et. al., 2016). Once it

reach the lysosome, the autophagosome, with attachment of a SNARE (soluble

N-ethylmaleimide-sensitive-factor attachment protein receptor), cause fusion of both lysosome

and autophagosome to form autolysosomes (also called autophagolysosomes and

amphisomes; Deretic, Saitoh & Akira, 2013). The autolysosomes lumen is acidified and then the

intracellular material are digested by lysosomal enzymes (Deretic, Saitoh & Akira, 2013). After

all material degraded in the autolysosomes, the autolysosomes would act as a secondary

lysosome and able to fuse with a different autophagososome (Eskelinen & Saftig, 2009). If the

degradation process is incomplete, then the autolysosomes would inhabit the cytoplasm

(Eskelinen & Saftig, 2009).

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 Termination of autophagy

Termination of autophagy occurs by the reactivation of mTORC1 (He & Klionsky, 2009).

This feedback mechanism prevent the excessive activation of autophagy during starvation.

Autophagy and the immune system

Although autophagy is necessary for energy restoration during a nutrient deficiency

environment, the process is involved in many other biological events, such as immune response

and aging.

The earliest case reported, in regards to the association of autophagy and the immune

system, was in 1984. Rikihisa noted that autophagy was induced during Rickettsial infection. As

new technologies emerged, it was apparent that autophagy is essential for an effective innate

immunity. To understand the relationship between the innate immune system and autophagy, a

general understanding of the innate immune system must be established.

The innate immunity is the first line of defense. In this system, there are innate immune

cells called sentinel cells which circulate around the body to detect potential hazards (Murphy,

2011). These sentinel cells can detect danger through a specific receptor called pathogen

recognition receptor (PRR) (Murphy, 2011). PRR recognize two classes of molecules:

pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns

(DAMPs) (Murphy, 2011). PAMPs are molecules associated with the pathogen, while DAMPs

are molecules released by necrotic cells (Murphy, 2011). After these PAMPs or DAMPs

molecules are recognized by PRR, a cascade of event occurs, leading to the release of

proinflammatory cytokines and chemoattractants (Murphy, 2011).

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 Autophagy can be activated by PRR and autophagic adaptor protein to eliminate

pathogens (Deretic, Saitoh & Akira, 2013). Another ways of activation of autophagy include

inflammatory cytokines induced-autophagy (Deretic, Saitoh & Akira, 2013). There are some

pathogens that are able to escape the fate of autophagy. For example, some bacteria can

produce toxin to inhibit the activation of autophagy through interfering a pathway. However,

such pathway is beyond the scope of this paper.

Autophagy, aging and longevity

As an individual ages, there is a progressive accumulation of damaged proteins and

organelles (Yang & Klionsky, 2010). In addition, there is a decrease of autophagic activities with

age (Yang & Klionsky, 2010). With such autophagic activities reduction and accumulation of

undegraded material, an individual will be prone to various of diseases. However, it was shown

that restricted caloric diet slowed down aging and prevent decline in autophagic activity (Yang &

Klionsky, 2010). There are more interest facts on how autophagy work as one ages; however,

such discussion is beyond the scope of this paper.

Closing Remarks

Our understanding of the biology of autophagy and it relevance to human health and

disease is continue to progress. We know a lot about the process of how a phagophore goes

from a autophagosome to an autolysosomes. With this information, we can develop a

therapeutic drug to improve autophagic activities to combat various diseases, such

neurodegenerative diseases, cancers, infectious diseases, metabolic diseases, cardiac

diseases, and even aging. However, there is still a lot we do not know. How phagophore

elongates? What other proteins are involved in this process? All and all, research are continuing

to help elucidate the autophagic mechanism, and reveal connection with diseases and possibly

treatments.

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