Autophagy and the Integrated Stress Response

doi:10.1016/J.MOLCEL.2010.09.023

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Autophagy and the Integrated Stress Response

Journal Article•DOI•

Autophagy and the Integrated Stress Response

Guido Kroemer¹, Guillermo Mariño¹, Guillermo Mariño², Beth Levine³•Institutions (3)

French Institute of Health and Medical Research¹, Institut Gustave Roussy², University of Texas Southwestern Medical Center³

22 Oct 2010-Molecular Cell (Cell Press)-Vol. 40, Iss: 2, pp 280-293

TL;DR: Autophagy is a cell biological process that is a central component of the integrated stress response and can be integrated with other cellular stress responses through parallel stimulation of autophagy and other stress responses by specific stress stimuli.

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About: This article is published in Molecular Cell.The article was published on 2010-10-22 and is currently open access. It has received 3002 citations till now. The article focuses on the topics: Integrated stress response & Autophagy.

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Journal Article•DOI•

Autophagy: Renovation of Cells and Tissues

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Noboru Mizushima¹, Masaaki Komatsu²•Institutions (2)

Tokyo Medical and Dental University¹, Institute of Medical Science²

11 Nov 2011-Cell

TL;DR: It is explored how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease.

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4,529 citations

Cites background from "Autophagy and the Integrated Stress..."

...Limitation of various types of nutrients, such as amino acids, growth factors, oxygen, and energy, can induce autophagy (He and Klionsky, 2009; Kroemer et al., 2010)....
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...Limitation of various types of nutrients, such as amino acids, growth factors, oxygen, and energy, can induce autophagy (He and Klionsky, 2009; Kroemer et al., 2010)....
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Journal Article•DOI•

The unfolded protein response: controlling cell fate decisions under ER stress and beyond

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Claudio Hetz¹•Institutions (1)

University of Chile¹

01 Feb 2012-Nature Reviews Molecular Cell Biology

TL;DR: Insight is provided into the regulatory mechanisms and signalling crosstalk of the three branches of the UPR, which are initiated by the stress sensors protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF6).

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Abstract: Protein-folding stress at the endoplasmic reticulum (ER) is a salient feature of specialized secretory cells and is also involved in the pathogenesis of many human diseases. ER stress is buffered by the activation of the unfolded protein response (UPR), a homeostatic signalling network that orchestrates the recovery of ER function, and failure to adapt to ER stress results in apoptosis. Progress in the field has provided insight into the regulatory mechanisms and signalling crosstalk of the three branches of the UPR, which are initiated by the stress sensors protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF6). In addition, novel physiological outcomes of the UPR that are not directly related to protein-folding stress, such as innate immunity, metabolism and cell differentiation, have been revealed.

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3,027 citations

Cites background from "Autophagy and the Integrated Stress..."

...Macroautophagy, a bulk degradation pathway, is also activated by ER stress, possibly to eliminate damaged ER (a process termed ER-phagy) and abnormal protein aggregates through the lysosomal pathwa...
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Journal Article•DOI•

Autophagy in immunity and inflammation

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Beth Levine¹, Noboru Mizushima², Herbert W. Virgin³•Institutions (3)

University of Texas Southwestern Medical Center¹, Tokyo Medical and Dental University², Washington University in St. Louis³

20 Jan 2011-Nature

TL;DR: A crucial role is revealed for the autophagy pathway and proteins in immunity and inflammation, and they balance the beneficial and detrimental effects of immunity andinflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.

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Abstract: Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway is adaptation to nutrient deprivation. However, in complex multicellular organisms, the core molecular machinery of autophagy - the 'autophagy proteins' - orchestrates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Recent developments reveal a crucial role for the autophagy pathway and proteins in immunity and inflammation. They balance the beneficial and detrimental effects of immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.

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2,757 citations

Cites background or result from "Autophagy and the Integrated Stress..."

...This leads to the recruitment of the class III phosphatidylinositol-3-OH kinase (PI(3)K) complex, which includes at least VPS34 (also known as PIK3C3), VPS15 (PIK3R4 and p150), beclin 1 and ATG14, to the ER(13,14)....
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...DFCP1 is diffusely present on the ER or the Golgi, but translocates to the autophagosome formation site in a PtdIns(3)P-dependent manner to generate ER-associated Ω-like structures termed omegasomes15....
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...The PI(3)K complex produces phosphatidylinositol-3-phosphate (PtdIns(3)P), which recruits effectors such as double FYVE-containing protein 1 (DFCP1) and WDrepeat domain phosphoinositide-interacting (WIPI) family proteins....
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...After induction of autophagy, the ULK1 complex (ULK1–ATG13–FIP200–ATG101) (downstream of the inhibitory mTOR signalling complex) translocates to the ER and transiently associates with VMP1, resulting in activation of the ER-localized autophagy-specific class III phosphatidylinositol-3-OH kinase (PI(3)K) complex, and the phosphatidylinositol-3-phosphate (PtdIns(3)P) formed on the ER membrane recruits DFCP1 and WIPIs....
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...DFCP1 PtdIns(3)P-binding ER protein Unknown...
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Journal Article•DOI•

Immunogenic Cell Death in Cancer Therapy

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Guido Kroemer, Lorenzo Galluzzi, Oliver Kepp, Laurence Zitvogel

21 Mar 2013-Annual Review of Immunology

TL;DR: It is postulate that ICD constitutes a prominent pathway for the activation of the immune system against cancer, which in turn determines the long-term success of anticancer therapies and its subversion by pathogens.

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Abstract: Depending on the initiating stimulus, cancer cell death can be immunogenic or nonimmunogenic. Immunogenic cell death (ICD) involves changes in the composition of the cell surface as well as the release of soluble mediators, occurring in a defined temporal sequence. Such signals operate on a series of receptors expressed by dendritic cells to stimulate the presentation of tumor antigens to T cells. We postulate that ICD constitutes a prominent pathway for the activation of the immune system against cancer, which in turn determines the long-term success of anticancer therapies. Hence, suboptimal regimens (failing to induce ICD), selective alterations in cancer cells (preventing the emission of immunogenic signals during ICD), or defects in immune effectors (abolishing the perception of ICD by the immune system) can all contribute to therapeutic failure. We surmise that ICD and its subversion by pathogens also play major roles in antiviral immune responses.

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2,323 citations

Journal Article•DOI•

Physiological roles of mitochondrial reactive oxygen species.

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Laura A. Sena¹, Navdeep S. Chandel¹•Institutions (1)

Northwestern University¹

26 Oct 2012-Molecular Cell

TL;DR: More and more evidence suggests that mROS are critical for healthy cell function, and this evidence is discussed following some background on the generation and regulation ofmROS.

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2,038 citations

Cites background from "Autophagy and the Integrated Stress..."

...In addition to its role in maintenance of homeostasis, autophagy is also an important response to cellular stress, including starvation, ischemia/reperfusion, and pathogen infection (Kroemer et al., 2010; Levine et al., 2011)....
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References

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Journal Article•DOI•

Autophagy in the Pathogenesis of Disease

[...]

Beth Levine¹, Guido Kroemer², Guido Kroemer³, Guido Kroemer⁴•Institutions (4)

University of Texas Southwestern Medical Center¹, University of Paris-Sud², French Institute of Health and Medical Research³, Institut Gustave Roussy⁴

11 Jan 2008-Cell

TL;DR: This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.

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6,301 citations

"Autophagy and the Integrated Stress..." refers background in this paper

...Autophagy constitutes a major protective mechanism that allows cells to survive in response to multiple stressors and that helps defend organisms against degenerative, inflammatory, infectious, and neoplastic diseases (Levine and Kroemer, 2008; Mizushima et al., 2008)....
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...Moreover, there is a strong correlation between mitogenic signaling and autophagy inhibition (Levine and Kroemer, 2008)....
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Journal Article•DOI•

Autophagy fights disease through cellular self-digestion

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Noboru Mizushima¹, Beth Levine², Ana Maria Cuervo³, Daniel J. Klionsky⁴•Institutions (4)

Tokyo Medical and Dental University¹, University of Texas at Dallas², Yeshiva University³, University of Michigan⁴

28 Feb 2008-Nature

TL;DR: Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health, and to play a role in cell death.

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Abstract: Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.

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5,831 citations

Journal Article•DOI•

Methods in Mammalian Autophagy Research

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Noboru Mizushima¹, Tamotsu Yoshimori², Beth Levine³•Institutions (3)

Tokyo Medical and Dental University¹, Osaka University², University of Texas Southwestern Medical Center³

05 Feb 2010-Cell

TL;DR: Methods to monitor autophagy and to modulate autophagic activity are discussed, with a primary focus on mammalian macroautophagy.

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3,998 citations

"Autophagy and the Integrated Stress..." refers background in this paper

...The lipidated form of LC3 is stably associated with the autophagosome membrane, and its biochemical and microscopic detection is widely used to measure cellular autophagy (Mizushima et al., 2010) (Figure 1C)....
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Journal Article•DOI•

Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy.

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Sophie Pattingre¹, Sophie Pattingre², Amina T. Tassa², Xueping Qu¹, Xueping Qu², Rita Garuti², Xiao Huan Liang¹, Noboru Mizushima³, Milton Packer², Michael D. Schneider⁴, Beth Levine², Beth Levine¹ - Show less +8 more•Institutions (4)

Columbia University¹, University of Texas Southwestern Medical Center², Institute of Medical Science³, Baylor College of Medicine⁴

23 Sep 2005-Cell

TL;DR: Bcl-2 not only functions as an antiapoptotic protein, but also as an antiautophagy protein via its inhibitory interaction with Beclin 1, which may help maintain autophagy at levels that are compatible with cell survival, rather than cell death.

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3,384 citations

"Autophagy and the Integrated Stress..." refers background in this paper

...In addition, it is plausible that the liberation of Bcl-2 and FLIP from activated autophagy protein complexes may free up these molecules to block the intrinsic and extrinsic pathways of apoptosis, respectively (Lee et al., 2009; Pattingre et al., 2005)....
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...Anti-apoptotic family members (such as Bcl-2, Bcl-XL and Mcl-1) are also important negative regulators of autophagy through an inhibitory interaction of their BH3-binding groove with the BH3 domain of Beclin 1 (Maiuri et al., 2007; Pattingre et al., 2005) (Fig....
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...Antiapoptotic family members (such as Bcl-2, Bcl-XL, and Mcl-1) are also important negative regulators of autophagy through an inhibitory interaction of their BH3-binding groove with the BH3 domain of Beclin 1 (Maiuri et al., 2007; Pattingre et al., 2005) (Figure 2B)....
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Journal Article•DOI•

Mitochondrial Membrane Permeabilization in Cell Death

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Guido Kroemer¹, Lorenzo Galluzzi, Catherine Brenner•Institutions (1)

French Institute of Health and Medical Research¹

01 Jan 2007-Physiological Reviews

TL;DR: Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria, meaning that mitochondria coordinate the late stage of cellular demise.

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Abstract: Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

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3,340 citations

"Autophagy and the Integrated Stress..." refers background in this paper

...The intrinsic pathway of apoptosis is initiated by mitochondrial membrane permeabilization (MMP) (Kroemer et al., 2007)....
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...Indeed, mitochondrial membrane permeabilization (MMP) constitutes one of the hallmarks of imminent apoptotic or necrotic cell death (Kroemer et al., 2007)....
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