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Location: Home > Information Center > Technical FAQs > Autophagy Technology Column > Autophagy concept and basic process

Autophagy concept and basic process

Date: 2015-11-23 Author: Leading Biology Click: 879

Sweden Karolinska Institute announced the winner who won the 2016 Nobel Prize in Physiology or Medicine in the capital Stockholm at 17:30, Beijing Time. Japanese scientist Yoshinori Ohsumi won the 2016 Nobel Price for Physiology or Medicine for the studying on 「autophagy」.


What is autophagy? What is the concept and basic process of autophagy? Now let me show you!


Finding of autophagy

Belgian scientist Christian de Duve observed autophagosome structure through electron microscope, and came up with the statement, 「autophagy」 at the 1963 CIBA Foundation Symposium on Lysosomes for the first time. Therefore, he is recognized well for the ancestor in autophagy studying. He also won the 1974 Nobel Prize for the finding of lysosome.


Classification

Autophagy is divided into three types according to the occurring process now: Macroautophagy, Microautophagy and Chaperone-mediated autophagy (CMA). The autophagy means Macroautophagy in general, and refers to the first type unless otherwise mentioned.


Concept and basic process

Autophagy is a 「Self-eating」 phenomenon in cells, and apoptosis is a 「Self-killing」 phenomenon. They share the same stimulating factors and regulatory proteins, while with different trigger threshold, and the mechanism in transition and coordination is not clear at present. Autophagy means the membrane(the source is disputed now, most are double layer membrane, while some are multilayer or monolayer membrane) forms an autophagosome by wrapping parts of the cytoplasm and the organelles and proteins which need to degrade, then forms so-called amphisomes with endosome, and finally froms autophagolysosome by fusion with lysosome and degrade the content in the membrane to achieve the cell homeostasis and renew the organelles.


Gene

Autophagy-related gene (ATG) clone started in yeast. The first yeast ATG was cloned by Japanese scientist Yoshinori Ohsumi team in 1997, named Atg1, and the paper was published on 《Gene》. The first mammal ATG was cloned by American scientist Beth Levine team, named Beclin1, and was published on 《J Virol》 with the first author Xiao Huan Liang. Up to September 2010, 34 ATG have been cloned.


Function

It is widely believed that autophagy is a kind of defense and stress regulatory mechanism. Cells could remove、degrade and digest some damaged、 denatured、 aging and disabled cells、 organelles and some biomacromolecules such as denatured proteins and nucleic acids through autophagy and lysosome. This process could provide necessary material for reconstruction、 regeneration and repair, achieving recycle and reuse in cells. It is both 「refuse processing plant」 and 「reclamation depot」 in vivo; it can not only resist the pathogen invasion, but protect the cells from damaging by intracellular toxicants. Therefore, generally speaking, apoptosis is programmed cell death, and autophagy is programmed cell survival. But too much or too less autophagy could harm cells. In some circumstances, autophagy could lead to cell death. So autophagy was called Type Ⅱ programmed cell death in some early papers, but it is a misnomer now.


Detect methods

Golden standard is observe autophagosome with membrane structure or other subcellular structures related through electron microscope. The most common method is to detect the transform of autophagy marker LC3 (LC3-II/LC3-I) using western blot or monitor the formation of LC3 puncta under the fluorescence microscope. Since LC3 itself would degrade via lysosome, some lysosome inhibitors needs to be combined to monitor jointly. Moreover, a paper published on 《Nature》 in 2009 verified LC3-independent pathway autophagy exists.


Research hotspots

The most forefront three fields are: 1) The source of autophagosome membrane; 2) Organelle autophagy,especially mitophagy; 3) The formation of the Beclin1 complex and the function of the regulatory proteins and mTOR signal pathway in autophagy.


Disease models

Autophagy plays an important role in immune、 infection、 inflammation、 tumor、 cardiovascular disease and neurodegenerative disease attack in organism. The hottest three diseases are tumor、 neurodegenerative disease and immunological disease. The function in tumor is the most controversial field. It’s a double-edged sword, mainly reflected in the increase of the spontaneous tumor in the animals with ATGs knockdown. But on the contrary, after knockdown ATGs, the sensitivity of the chemotherapy、 radiotherapy and immunotherapy increased.


Paper with high exposure rates published on top journals is mainly from the reseach teams leading by 5 scientists below.

1)Dr. Yoshinori Ohsumi, Japanese scientist, who cloned the first yeast autophagy-related gene Atg1 and LC3. His achievements were mainly studied in the yeast model;

2)Dr. Daniel J. Klionsky, American scientist, whose achievements were mainly studied in the yeast model. He introduced autophagy in a review published on 《Science》 first, and established 《Autophagy》, the first journal about autophagy (http://www.landesbioscience.com/journals/autophagy/). He held First Autophagy International Conference, and made a great contribution in autophagy publicity;

3)Dr. Noboru Mizushima, a Japanese scientist. He reported Atg5 function in 2001, which was considered as the first step for the mammal molecular mechanism research. He also joined the autophagy marker LC3 cloning, and prepared some ATG knockdown mice and LC3 genetically modified mice. He may win the Nobel Prize.

4)Dr. Beth Levine, American scientist, who cloned the first mammal autophagy-related gene Beclin1;

5)Dr. Guido Kroemer, French scientist, whose paper was most widely cited in cell autophagy and death. He made outstanding contributions in the apoptosis research and wide covered. He also works on autophagy, such as p53, Bcl2 family and autophagy.

6)Dr. Tamotsu Yoshimori, Japanese scientist, who was the corresponding author of the paper about cloning the autophagy marker LC3, which is widely used. He also took part in the research about the mechanism of ATG5 in 2010, and he was one of the corresponding authors. He makes great contributions in methodology, too. Now he studies ATG14 and ATG16 mainly and may win the Nobel Prize.

It’s worth noting that the three Japanese scientists above collaborate closely, and cloned most ATGs until now. They often share corresponding authors.

7)Dr. Patrice Codogno, French scientist, who verified the function of PI3K signal pathway in autophagy、 Type I anti-autophagy and Type III anti-autophagy. He is the pioneer in autophagy signal pathway.

8)Dr. Ana Maria Cuervo, American scientist, is the pioneer in molecular chaperones autophagy.

9)Dr. David Rubinsztein, English scientist, who found that inhibit mTOR promotes autophagy in 2004, and this discovery reported the relationship between mTOR and autophagy firstly. He used rapamycin to induce autophagy, and it has became one of the classical models. In 2010, he verified the negative feedback fuction of autophagy on mTOR firstly and published on 《Nature》.

In a word, these scientist above control this field and form domanial effects. They define and correct autophagy related concepts and leading this field. By focusing on their review often, you could keep up with the progress about the entire field of autophagy.

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