Apoptosis & Autophagy

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1 SPETSAI SUMMER SCHOOL 2010 Host Microbe Interactions Cellular Response to Infection: Apoptosis & Autophagy Christoph Dehio

2 There are many ways to die

3 Apoptosis: Historical perspective Process of programmed cell death In 1842, the German scientist Carl Vogt was first to describe the principle In 1885, anatomist Walther Flemming delivered a more precise description of the process In 1965 the topic was resurrected The use of the term apoptosis for the description of programmed cell death was coined in 1972 Carl Vogt Walther Flemming

4 Apoptosis: Historical perspective

5 Apoptosis: Historical perspective

6 Apoptosis: Historical perspective

7 Apoptosis: Historical perspective

8 Apoptosis: morphological changes Gerard Evan and Joshua Goldstein

9 Apoptosis: morphological changes Gerard Evan and Joshua Goldstein

10 Gerard Evan and Joshua Goldstein Apoptosis: Sequence of events Cytochrom C (CytC) Phosphatidyserine (PS) DNA

11 Apoptosis: Sequence of events Cytochrom C (CytC) Phosphatidyserine (PS) DNA Gerard Evan and Joshua Goldstein

12 Apoptosis: Sequence of events Cytochrom C (CytC) Phosphatidyserine (PS) DNA Gerard Evan and Joshua Goldstein

13 Byrne and Ojcius (2004) Nat. Rev. Microbiol. Apopotsis: Mechanism Sequential activation of cysteine-dependent aspartate-specific proteases (caspases) Initiator caspases: 2, 8, 9, 10 Effector caspases: 3, 6, 7 Independent of caspase 1 Regulated processes Extrinsic: stimulation of Fas or TNFR surface receptors Intrinsic: altered mitochondrial membrane integrity

14 Pathogen-triggered apopotsis: The Shigella paradigm Zychlinsky et al. (1992) Nature Philippe Sansonetti Arturo Zychlinski

15 Pathogen-triggered PCD (apopotsis): The Shigella paradigm Schroeder and Hilbi (2008) Clin. Microbiol. Rev.

16 Pyroptosis Greek: pyro = fire or fever; ptosis = falling morphologically and mechanistically distinct form of programmed cell death no cytochrome C release independent from caspase-3, -6 and -8 mediated by activation of caspase-1 activates inflammatory cytokines IL-1ß and IL-18 rapid plasma-membrane rupture and release of cytoplasmic content induced by various intra- und extracellular

17 Dual recognition of PAMPs Vance et al. (2009) Host Cell Microbiol.

18 Pyroptosis & danger signal sensing Bergsbaken et al. (2009) Nat. Rev. Microbiol.

19 Pathogen-sensing for pyroptosis by direct interaction of bacterial ligands with caspase 1: Shigella (IpaB) Salmonella (SipB) via Nod-like receptors (NLRs): NLRC4/IPAF: Pseudomonas Salmonella (flagellin via T3SS; T3SS components) Listeria (flagellin during intracytoplasmic state) Shigella NAIP5 Legionella (flagellin) Hersh et al. (1999) PNAS Franchi et al. (2006) Nat. Immunol. Miao et al. (2006) Nat. Immunol. Molofsky et al. (2006) J. Exp. Med. Ren et al. (2006) PLoS Pathog. Zamboni et al. (2006) Nat. Immunol. Sun et al. (2007) J. Biol. Chem. Lightfield et al. (2008) Nat. Immunol. Warren et al. (2008) J. Immunol. Vance et al. (2009) Cell Host Microbe Miao et al. (2010) PNAS

20 Pyroptosis & inflammosome Jürg Tschopp Activated caspase 1 Salmonella DNA Bergsbaken et al. (2009) Nat. Rev. Microbiol.

21 Bergsbaken et al. (2009) Nat. Rev. Microbiol. Pyroptosis - an inflammatory host response

22 Pyroptosis - an inflammatory host response

23 Pathogen- and host modulation of Bergsbaken et al. (2009) Nat. Rev. Microbiol. caspase 1 activation

24 Apoptosis: friend or foe Host view Apoptosis is bad unless it takes away a privileged intracellular niche Pathogen view Inhibit apoptosis to provide for intracellular niche (Chlamydia) Promote apoptosis (Yersinia, Shigella) Dismantles host defenses Promote microbe dissemination Many bacterial molecules can modulate apoptosis Toxins

25 Faherty and Morelli (2008) Trends Microbiol. Classification of bacteria that inhibit apoptosis

26 Faherty and Morelli (2008) Trends Microbiol. Classification of bacteria that inhibit apoptosis

27 Chlamydia & Apoptosis regulation Pirbhai et al. (2006) JBC Byrne and Ojcius (2004) Nat. Rev. Microbiol.

28 Chlamydia & Apoptosis regulation Pirbhai et al. (2006) JBC Byrne and Ojcius (2004) Nat. Rev. Microbiol.

29 Chlamydia & Apoptosis regulation Chlamydiae-infected cells are protected against mitochondria-dependent cell death but not caspase-3 mediated cell death Inhibits cytochrome C release CPAF degrades pro-apoptotic BH3 domain containing proteins (Bim/Bod, Puma, Bad) upstream of Bax/Bak Pirbhai et al. (2006) JBC Byrne and Ojcius (2004) Nat. Rev. Microbiol.

30 Chlamydia & Apoptosis regulation Chlamydiae-infected cells are protected against mitochondria-dependent cell death but not caspase-3 mediated cell death Inhibits cytochrome C release CPAF degrades pro-apoptotic BH3 domain containing proteins (Bim/Bod, Puma, Bad) upstream of Bax/Bak Chlamydia protein associated with death domains, that interacts with death domains of TNF receptors to activate apoptotic caspases Pirbhai et al. (2006) JBC Byrne and Ojcius (2004) Nat. Rev. Microbiol.

31 Cell death as microbial exit strategy Hybiske and Stephens (2008) Nat. Rev. Microbiol.

32 There are many ways to die

protects cells against starvation and microbe invasion Three types:

33 Autophagy Autophagy eat oneself Xenophagy eat foreign matter Highly conserved and regulated process that maintains cellular homeostasis and protects cells against starvation and microbe invasion Three types: macroautophagy microautophagy chaperone-mediated autophagy Jia et al., 1997, Brit. J. Haematol.

34 The many functions of autophagy Evolutionary conserved from yeast to man Executed by a set of about 20 conserved proteins Yoshimori (2008) Cell

35 Autophagy: Mechanism Deretic (2005) Trends Immunol.

36 Autophagy: Evolutionary view Deretic (2010) Curr. Opin. Cell Biol.

37 Shigella and autophagy From Schoeder and Hilbi (2008) Clin. Microbiol. Rev. Ogawa et al. (2005) Science

38 Shigella and autophagy Dupont (2009) Cell Host&Microbe Hilbi (2009) Cell Host&Microbe

39 Adapters targeting bacteria and mitochondria for autophagic degradation Yoshikawa (2009) Nat. Cell Biol. Thurston et al. (2009) Nat. Immunol. Dupont (2009) Cell Host&Microbe Zheng (2009) J. Immunol. Thurston et al. (2009) Nat. Immunol. Deretic (2010) Curr. Opin. Cell Biol.

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43 There are many ways to die

Apoptosis EXTRA REQUIREMETS

Apoptosis EXTRA REQUIREMETS Apoptosis Introduction (SLIDE 1) Organisms develop from a single cell, and in doing so an anatomy has to be created. This process not only involves the creation of new cells, but also the removal of cells