Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Mar;15(3):129-38.
doi: 10.1016/j.molmed.2009.01.002. Epub 2009 Feb 21.

When apoptosis meets autophagy: deciding cell fate after trauma and sepsis

Ya-Ching Hsieh  1 , Mohammad Athar, Irshad H Chaudry
Affiliations

When apoptosis meets autophagy: deciding cell fate after trauma and sepsis

Ya-Ching Hsieh et al. Trends Mol Med. 2009 Mar.

Abstract

Apoptotic cell death is considered to be an underlying mechanism in immunosuppression and multiple organ dysfunction after trauma-hemorrhage and sepsis. Although studied intensively over the last decade, the role of other cell death mechanisms under similar pathophysiological conditions has remained elusive. Recently, autophagy has emerged as an important mediator of programmed cell death pathways. Here, we review recent advances in our understanding of apoptosis and autophagy and the crosstalk between these processes. We explore the coexistence of these two processes and the effects of autophagy on apoptosis after trauma-hemorrhage and sepsis. The inter-relationship between autophagy and apoptosis might unveil novel therapeutic approaches for the detection and treatment of trauma-hemorrhage and sepsis.

PubMed Disclaimer

Conflict of interest statement

Disclosure statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Induction of autophagy contributing to cell survival or death during apoptosis. Low levels of autophagy can promote survival by eliminating intracellular damaged proteins and organelles, apoptotic cell corpses and bacteria in keeping with its primary function as a cytoplasmic clean-up process. It can also regulate immune-cell function and inflammation. This process can increase cell survival by preventing cell apoptosis. However, excessive and long-term upregulation of autophagy eventually leads to destruction of essential proteins and organelles beyond a certain threshold, resulting in cell death. This prolonged upregulation can lead to apoptosis activation.
Figure 2
Figure 2
Regulation of autophagy and apoptosis. (a) Autophagy. Induction of autophagy requires activity of Beclin1 and its interacting partner, class III phosphoinositide 3 kinase (PI3K), also known as Vps34. Bcl-2/BclXL, can bind to Beclin1 and inhibit autophagy. By contrast, autophagy is negatively regulated by class I PI3K through mammalian target of rapamycin (mTOR). The elongation and shape of autophagosomes are controlled by two protein (and lipid) conjugation systems, namely the autophagy-related gene (ATG)12 pathway and the microtubule-associated protein 1 light chain 3 (LC3 or ATG8)–phosphatidylethanolamine (PE) pathway. These pathways are similar to the ubiquitin conjugation systems and include E1-activating and E2-conjugating enzymes. ATG12 is a first modifier that is essential for the formation of autophagosomal precursors and isolation membranes. ATG12 is activated by ATG7 (an E1 ubiquitin-like enzyme), transferred to ATG10 (an E2 ubiquitin-like enzyme) and conjugated to ATG5, which subsequently forms a complex with ATG16. The membrane-bound ATG12–ATG5–ATG16 complex is a prerequisite for recruitment of LC3-II, the product of the second ubiquitin-like conjugation. Initially, LC3 is cleaved by the protease ATG4 to generate LC3-I. LC3-I is then activated by ATG7, transferred to ATG3 (a second E2 ubiquitin-like enzyme) and conjugated to PE. The resulting LC3-II is recruited into the forming autophagosomal membrane. The Beclin-1–Vps34 autophagy complex can be inhibited by another Beclin-1-interacting partner, the anti-apoptotic protein Bcl-2. After completion of autophagosome formation, a second cleavage by ATG4 results in some removal of PE from LC3-II, reverting it into LC3-I, which is released from the membrane. The remaining membrane-attached LC3-II is degraded by lysosomal proteases. The LC3-II:LC3-I ratio has been demonstrated to correlate with the extent of autophagosome formation. (b) Signaling and processes of autophagy and apoptosis. Autophagy: cytosol, containing proteins or organelles (such as damaged mitochondria), is sequestered by an expanding membrane. This double-membrane structure fuses with the lysosome to form an autolysosome, generating the autophagolysosome. Apoptosis: the extrinsic pathway is mediated by caspase-8, whereas the intrinsic pathway is mediated by caspase-9. FADD (FAS-associated via death domain), an adaptor protein that couples death receptors (such as CD95) and Bcl-2/BclXL, inhibits the loss of mitochondrial membrane potential. Cytochrome c is released from the mitochondria and forms the apoptosome together with apoptotic-protease-activating factor 1 (APAF1) and pro-caspase-9. Active caspase-9 and caspase-8 can activate caspase -3, leading to cell death apoptosis.
Figure 3
Figure 3
The regulation of autophagy in adaptive immunity. Autophagy might be involved in adaptive immunity by delivering antigens into the MHC class II loading compartment (MIIC). In MIICs, the antigen is processed and loaded onto MHC class II molecules for CD4+ T-cell stimulation. Activated CD4+ T cells can then enhance autophagy and autophagosome–lysosome fusion via IFN-γ and TNF family members (such as TNF, CD40L and TRAIL). In addition, autophagy is negatively regulated by the Th2-type cytokine IL-3.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Smith JW, et al. Immunologic responses to critical injury and sepsis. J Intensive Care Med. 2006;21:160–172. - PubMed
    1. Brunn GJ, Platt JL. The etiology of sepsis: turned inside out. Trends Mol Med. 2006;12:10–16. - PubMed
    1. Ulloa L, Tracey KJ. The ‘cytokine profile’: a code for sepsis. Trends Mol Med. 2005;11:56–63. - PubMed
    1. Venet F, et al. Regulatory T cell populations in sepsis and trauma. J Leukoc Biol. 2008;83:523–535. - PubMed
    1. Hotchkiss RS, Nicholson DW. Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol. 2006;6:813–822. - PubMed

Publication types