Elsevier

Life Sciences

Volume 188, 1 November 2017, Pages 53-67
Life Sciences

Review article
Autophagy: The spotlight for cellular stress responses

https://doi.org/10.1016/j.lfs.2017.08.029Get rights and content

Abstract

Autophagy is an essential cellular mechanism which plays “housekeeping” role in normal physiological processes including removing of long lived, aggregated and misfolded proteins, clearing damaged organelles, growth regulation and aging. Autophagy is also involved in a variety of biological functions like development, cellular differentiation, defense against pathogens and nutritional starvation. The integration of autophagy into these biological functions and other stress responses is determined by the transcriptional factors that undertake the regulatory mechanism. This review discusses the machinery of autophagy, the molecular web that connects autophagy to various stress responses like inflammation, hypoxia, ER stress, and various other pathologic conditions. Defects in autophagy regulation play a central role in number of diseases, including neurodegenerative diseases, cancer, pathogen infection and metabolic diseases. Similarly, inhibiting autophagy would contribute in the treatment of cancer. However, understanding the biology of autophagy regulation requires pharmacologically active compounds which modulate the autophagy process. Inducers of autophagy are currently receiving considerable attention as autophagy upregulation may be a therapeutic benefit for certain neurodegenerative diseases (via removal of protein aggregates) while the inhibitors are being investigated for the treatment of cancers. Both induction and inhibition of autophagy have been proven to be beneficial in the treatment of cancer. This dual role of autophagy in cancers is now getting uncovered by the advancement in the research findings and development of effective autophagy modulators.

Section snippets

Presenting autophagy

In order to maintain a continuous protein turnover, there exists a constitutive proteasomal degradation system of proteins within the cell. But the system is known to be restricted to short-lived proteins present in the cell. Surprisingly, most of the cellular components are long lived. Therefore there must be an alternative recycling mechanism for the degradation of these macromolecules to promote adaptation and cell survival under adverse conditions. And autophagy was known to be very

The autophagy machinery

The whole mechanism of autophagy takes place in a well-known series of steps (Fig. 1) namely, Autophagosome formation, Selection of cargo, Autophagolysosome formation and Degradation. All these steps are very crucial for the autophagy process to take place successfully. Disruption of both earlier and later stages would equally affect the entire mechanism.

NF-κB links autophagy and inflammation

Mutations in the autophagy related genes were observed in inflammatory disease like Crohn's disease and other inflammation associated metabolic diseases [128]. During inflammation, there occurs an over expression of NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) at the inflamed sites which is induced by the transcription of pro-inflammatory genes to produce cytokines like TNFα and IL-1 [121]. Under normal condition, cells inactivate IKK, a major regulator of NF-κB to prevent

The ZKSCAN3-TFEB rival in autophagy regulation

ZKSCAN3 (Zinc finger protein with KRAB and SCAN domains 3) is a DNA-binding protein belonging to the zinc-finger family. It is involved in the transcriptional regulation of autophagy in that it represses the autophagy transcriptionally. Mounting evidences suggest that proteins functioning in autophagy (encoded by more than 60 genes) are transcriptionally modulated by ZKSCAN3. Under normal conditions, ZKSCAN3 localizes in the nucleus. In contrast, autophagy induction has led to the localization

Autophagy and cancer

Most of the autophagy regulators are oncogenes and tumor suppressors. And this is the reason behind the yet unknown role of autophagy in cancer [127]. A cell needs to undergo a change in the metabolic machinery to become cancerous. Autophagy is found to be down regulated in carcinogenesis. Cancer cells express a set of anti-autophagic genes like Bcl-2, AKT and PI3KC1 which makes it clear that autophagy serves as a hindrance for a normal cell in getting transformed into a cancerous one. Now the

Autophagy modulators at a glance

Recently, the development of autophagy modulators has become interests of many researchers to contribute to the better understanding of autophagy mechanism. Such research findings gave rise to effective modulators that are being successful in various stages of clinical trials.

Conclusion

Autophagy serves as a pro-survival mechanism for a cell in many cases. The process of autophagy is regulated by many regulators in vivo. And the integration of autophagy in different stress responses completely relies on the transcription factors that regulate the autophagy players functionally. The transcriptional factors like NF-κB are involved in multiple pathways and serve as better targets to target multiple signaling molecules via them. However, targeting the molecule in a functionally

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

The authors greatly acknowledge DST-SERB for the financial support through the Research Grant-SB/EMEQ-223/2014.

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