Modelling Autophagy in Cellular Processes

Monica Gupta, PhD
Tuesday, December 18th, 2018

Autophagy in Cellular Processes

Autophagy is derived from Greek and means self(auto)-eating(phagy). This process occurs in all eukaryotic cell types that contain a lysosomal compartment. In fact, basal autophagy contributes to long-lived protein degradation, organelle turnover in the cytoplasm, and the recycling of macromolecules to maintain bioenergetics1.

The purpose of autophagy is not solely the simple elimination of materials, but rather the dynamic recycling of cellular components that produces new building blocks and energy for cellular renovation and homeostasis1,2. The process of autophagy is conserved among yeast to mammals.

Macroautophagy begins with the formation of a cup-shaped double membrane structure that engulfs a portion of cytoplasm. This structure then encloses to form a mature vesicle called an autophagosome, which subsequently fuses with a lysosome, leading to the degradation of intra-autophagosomal components by lysosomal enzymes (Figure 1). Schematic overview of autophagy
Figure 1

Physiological and Pathological Roles of Autophagy

In mammals there are various diseases which result from impaired autophagy. What follows is a list of diseases associated with dysregulated autophagy2:

Organ-Tissue/Cell typeRole of AutophagyDisease associated with impaired autophagy
All cells-general functionConstitutive autophagy induced by starvation resulting in degradation of cytoplasmic contents into simpler productionAging, cell death2, cancer3
Brain-neurons & microgliaPrevention of protein aggregate formation, mitochondria degradation in microglial cells and neuronsParkinson's disease4
Alzheimer's disease4
Liver-hepatocytesPrevention of hepatocytes degradation; suppression of tumorsHepatocellular carcinoma2
Bone marrow-macrophages, dendritic cells, monocytesMaintenance of hematopoietic stem cells, degradation of intracellular pathogensMicrobial Infection and impaired immunity5
Lymphoid systemRegulation of cytokine productionMicrobial infection5
Pancreas- islets of langerhansB-cell adaptation to high fat dietDiabetes2
Adipose tissuesAdipogenesisObesity2
Intestine-paneth cellsAberrant expression of inflammatory cytokinesCrohn's disease2

Murine Models to Study Autophagy

One of the contributing factors for the increased knowledge of physiological roles of autophagy is availability of mouse models to study autophagy. Essentially, two types of gene-modified mouse models have played critical roles: "autophagy-monitoring mice"6 and "autophagy-deficient mice"7. Monitoring the autophagic process and measuring autophagic flux in different tissues and organelles is critical to investigate the function of autophagy under specific stimuli. Analysis of autophagy-deficient mice has led to conceptual findings in this field.

Taconic Biosciences offers various murine models to study diverse aspects of autophagy in different cell types.

Mouse ModelTaconic Model #Roles in Autophagy
Atg4b KOTF2950Atg4b is a member of ATG4-family cysteine proteases. These proteases have an important function as an essential factor in the Atg8 conjugation and deconjugation system, one of the unique mechanisms in autophagy. Inhibition of Atg4b results in inhibition of autophagy8.
Atg4c KOTF2255Atg4c is a member of ATG4-family cysteine proteases8.
Atg4d KOTF1385Atg4d is a member of ATG4-family cysteine proteases8.
TNFα Tg1006Tnfα induced autophagy play a critical role in induction of apoptosis/cell death in placental cells during pregnancy. Induction of autophagy has been implicated in placental dysfunction during pregnancies9.

TNFα induce autophagy in vitro and in vivo in osteoclasts of human rheumatoid arthritis (RA) thus regulating osteoclast differentiation and bone resorption and play a central role in RA10.
SumF1 KOTF3462Deficiency of SumF1 is associated with lysosomal storage disorders (LSDs) which results in severe neurodegeneration due to inability of degradation of intracellular proteins by the process of autophagy11.
Dram 2 KOTF3276Dram-2 interacts with central protein of autophagy LC3 to enhance autophagosome formation in DPN-mediated estrogen receptorβ activated autophagy in Hodgkin lymphoma (HL) cells. The induction of autophagy reduces 60% growth of lymphoma cells by inhibiting cell proliferation3.
Nlrp3 KO12935Autophagy keeps NLRP3 inflammasome activation in check by degrading oxidized mitochondria in macrophages thus limiting the NLRP3 inflammasome driven auto-inflammatory chronic inflammation12.
Pik3c3 KOTF1967Pik3c3 play a crucial role in mTOR driven autophagic lysosome reformation (ALR). Defects in the ALR process results in increase neuronal death13.
20452045Stat1 inhibits autophagy in mouse embryonic fibroblasts by transcriptional inhibition of the expression of a key autophagy protein ULK114.
CIEA NOG mouse ®NOGNOG mice were used to demonstrate the role of QSOX1 protein (Quiescin Sulfhydryl oxidase) in inhibiting tumor growth and progression in breast cancer cells by downregulating autophagy15.
Our understanding of autophagy and its role in different cellular processes has improved substantially over the past decade. Researchers have discovered connections between autophagy and cancer, neurodegeneration, and even lifespan extension. Availability and access to improved animal models are major contributing factors in the discovery and rapid progress in the field of autophagy.

1. Ravikumar, B. et al. Regulation of Mammalian Autophagy in Physiology and Pathophysiology. Physiological Reviews 90, 1383-1435 (2010).
2. Mizushima, N. & Komatsu, M. Autophagy: Renovation of Cells and Tissues. Cell 147, 728-741 (2011).
3. Pierdominici, M. et al. Estrogen receptor β ligation inhibits Hodgkin lymphoma growth by inducing autophagy. Oncotarget 8, (2017).
4. Lee, J.-A. Autophagy in neurodegeneration: two sides of the same coin. BMB reports 42, 324-330 (2009).
5. Levine, B., Mizushima, N. & Virgin, H. W. Autophagy in immunity and inflammation. Nature 469, 323-335 (2011).
6. Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T. & Ohsumi, Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Molecular biology of the cell 15, 1101-1111 (2004).
7. Komatsu, M. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. The Journal of Cell Biology 169, 425-434 (2005).
8. Maruyama, T. & Noda, N. N. Autophagy-regulating protease Atg4: structure, function, regulation and inhibition. The Journal of Antibiotics 71, 72-78 (2018).
9. Cha, H.-H. et al. Autophagy Induced by Tumor Necrosis Factor α Mediates Intrinsic Apoptosis in Trophoblastic Cells. Reproductive Sciences 21, 612-622 (2014).
10. Zheng, L. et al. Role of autophagy in tumor necrosis factor-α-induced apoptosis of osteoblast cells. Journal of Investigative Medicine 65, 1014-1020 (2017).
11. Settembre, C. et al. A block of autophagy in lysosomal storage disorders. Human Molecular Genetics 17, 119-129 (2008).
12. Zhong, Z., Sanchez-Lopez, E. & Karin, M. Autophagy, NLRP3 inflammasome and auto-inflammatory/immune diseases. Clin Exp Rheumatol 34, 12-6 (2016).
13. Munson, M. J. & Ganley, I. G. MTOR, PIK3C3, and autophagy: Signaling the beginning from the end. Autophagy 11, 2375-2376 (2015).
14. Goldberg, A. A. et al. Regulation of ULK1 Expression and Autophagy by STAT1. Journal of Biological Chemistry 292, 1899-1909 (2017).
15. Poillet, L. et al. QSOX1 Inhibits Autophagic Flux in Breast Cancer Cells. PLoS ONE 9, e86641 (2014).

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