线粒体在细胞防御微生物感染中的角色

Please cit Immunol ARTICLE IN PRESSG ModelYSMIM-717; No.of Pages10 Seminars in Immunology xxx (2009) xxx–xxx Contents lists available at ScienceDirect Seminars in Immunology journa l homepage: www.e lsev ier .com Review The role of mitochondria in cellular defense again Damien A E. a INSERM U542 lejuif C b Department o to, 1 K a r t i c l Keywords: Mitochondria Innate immun Viruses Bacteria Microbial path RIG-I MAVS NLRX1 ed fo orga nfecte mmu X1 an ction Detectio of pattern- responsible cellular lev ized in the (TLRs), and receptors (R lic sensors o DLM1/ZBP1 and caspase-1 inflammasome pathways, respectively [2,3]. Upon detection of the microbes by these PRMs, infected cells trigger a large repertoire of defense pathways that, together, contribute to cellular innate immunity. These responses include pathways such as NF-�B, JNK, p38 and ERK, which affect inflammatory and defenseme transcriptio some, resul mediators I response to Depending the infected lular respon Indeed, the the opposin a number o and the infe ∗ Correspon ∗∗ Correspon Toronto, Toron fax: +1 416 978 E-mail add Stephen.girard ocho ion o le in rpris ng m a co ens st p s an remain poorly characterized. In addition to the well-documented role of mitochondria in the induction of cell death pathways following infection, an emerging concept is that this organelle represents a convergent point of a number of cellular innate immune responses. This has 1044-5323/$ – doi:10.1016/j.s e this article in press as: Arnoult D, et al. The role of mitochondria in cellular defense against microbial infection. Semin (2009), doi:10.1016/j.smim.2009.05.009 diators at the transcriptional level. PRMs also trigger the n-independent recruitment of the caspase-1 inflamma- ting in the maturation of the critical pro-inflammatory L-1�, IL-18 and IL-33 [4]. Another critical axis of the host infection is themodulation of survival/death pathways. of the nature of the pathogen encountered, the nature of cell, and probably the intensity of the infection, the cel- ses are tipped either towards cell death or cell survival. final fate of an infected cell is commonly the result of g effects of pro-survival andpro-death pathways, and in f cases, depends on the opposite actions of the microbe cted cell. ding author. Tel.: +33 01 45 59 60 38; fax: +33 01 45 59 53 43. ding author at: Medical Sciences Building, Room 6336, University of to, Ontario, Canada M5S 1A8. Tel.: +1 416 978 7507; 5959. resses: Damien.arnoult@inserm.fr (D. Arnoult), in@utoronto.ca (S.E. Girardin). been remarkably illustrated recently by the discovery that MAVS (VISA/Cardif/IPS-1), a critical adaptor protein downstream of the RLR proteins Rig-I and Mda-5, is anchored to the mitochondrial outer membrane, and that this sub-cellular localization is essen- tial for the function of the protein [5,6]. These recent observations suggest that the role of mitochondria in the regulation of cellular responses to pathogens may span much beyond the modulation of cell death pathways. This article reviews some of the numerous roles of mitochondria in cellular innate immune defenses. 1. Mitochondrion, a key player in cell death pathways Apoptosis, a form of programmed cell death (PCD), is a cell suicide program essential for development and for adult tissue homeostasis in all metazoan animals. The misregulation (inhibi- tion or exacerbation) of PCD is associated with several pathologic conditions, includingneurodegenerativediseases, cancers andAIDS [7]. The stereotypical death throes of a cell undergoing apoptosis include DNA fragmentation, nuclear condensation, cell shrinkage, see front matter © 2009 Elsevier Ltd. All rights reserved. mim.2009.05.009 rnoulta,∗, Leticia Carneirob, Ivan Tattolib, Stephen , Hopital Paul Brousse, Batiment Lavoisier, 14 avenue Paul Vaillant Couturier, 94807 Vil f Laboratory Medicine and Pathobiology, Medical Sciences Building, University of Toron e i n f o ity ogenesis a b s t r a c t Mitochondria have been long recogniz it is therefore not surprising that this aiming to manipulate the fate of the i serve as a crucial platform for innate i known as IPS-1, VISA and Cardif), NLR tight interplay between microbial infe n of microbes by host cells relies on several families recognition molecules (PRMs), and these sensors are for the triggering of innate immune responses. At the el, three main families of PRMs have been character- past 15 years: the transmembrane Toll-like receptors the cytosolic Nod-like receptors (NLRs) and Rig-I-like LRs) [1]. In addition, an heterogenous class of cytoso- f double-stranded DNA is represented by the proteins and AIM2/HIN200, which trigger type I interferon Mit induct tral ro not su targeti despite pathog the mo by PRM / locate /ysmim st microbial infection Girardinb,∗∗ edex, France ing’s College Circle, Toronto, Ontario, Canada r their key role in themodulation of cell death pathways. Thus, nelle represents a recurrent target for pathogenic microbes, d host cell. More recently, mitochondria have been shown to ne signaling, as illustrated by the identification of MAVS (also d STING as mitochondrial proteins. This review discusses the , innate immune signaling and mitochondria. © 2009 Elsevier Ltd. All rights reserved. ndria represent a critical organelle implicated in the f cell death pathways and, consequently, play a cen- cellular host–microbial interactions. Therefore, it is ing that so many microbial strategies are aiming at itochondria to subvert cell death pathways. However, nsiderable literature on the interplay between host and at the level of the mitochondria, it is striking that, for art, the cellular pathways linking microbial detection d the induction of mitochondrial-dependent cell death, Please cit Immunol ARTICLE IN PRESSG ModelYSMIM-717; No.of Pages10 2 D. Arnoult et al. / Seminars in Immunology xxx (2009) xxx–xxx Fig. 1. The cen totic mitochondrial ctivat anti-apoptotic t inhib blebbing an are orchest called caspa Caspase duction and produced a produce act initiator cas caspases su Mitocho ways. The d involves m cellular dep dominantly Mitochondr genic factor [9] (Fig. 1). following t some that is cytochrome cesses effec cleaves sev Natural inh of apoptosi Omi/HtrA2, promote ca chondrial O in the relea subsequent anti-apopto or Bcl-XL in or Bak. Bcl- 2-homology required fo important s only’ protei The ‘BH3-o opto ax a 2, Bc ly m ed m rane the e po ucleo ther a spe g th tral role of mitochondrion in apoptosis and modulation by viral proteins. Pro-apop apoptogenic factors (cytochrome c, Smac/Diablo, Omi/HtrA2) involved in caspase a Bcl-2 members (Bcl-2 and Bcl-XL). In blue, the viral Bcl-2 homologues (vBcl-2) tha d phosphatidylserine externalization; these features rated by the activity of a family of cysteine proteases ses [8]. s are a family of cysteine proteases involved in the trans- execution of the apoptotic program [7]. Caspases are s pro-enzymes that must be proteolytically cleaved to ive caspases. Caspases are classified in two groups: the pases such as caspase-9 and caspase-8 and the effector ch as caspase-3. ndria are implicated in the two major apoptotic path- eath receptor-mediated pathway (“extrinsic pathway”) itochondria mainly as an amplification loop, whereas pro-ap bers (B as Bcl- 2 fami propos memb lowing putativ nine n to ano induce enablin e this article in press as: Arnoult D, et al. The role of mitochondria i (2009), doi:10.1016/j.smim.2009.05.009 rival and stress-mediated apoptosis is regulated pre- at the mitochondrial level (“intrinsic pathway”). ia have a pivotal role in apoptosis by releasing apopto- s such as cytochrome c, Smac/DIABLO and Omi/HtrA2 In the cytosol, cytochrome c triggers caspase activation he formation of a ternary complex called the apopto- composed of the adaptor protein Apaf-1, caspase-9 and c. In the apoptosome, active initiator caspase-9 pro- tor caspases such as caspase-3. Next, active caspase-3 eral cell substrates to induce apoptosis and cell death. ibitorsof caspasesare found incells, suchas the inhibitor s proteins (IAPs). A major function of Smac/DIABLO and once released into the cytosol, is to antagonize IAPs to spase activation. Bcl-2 family members regulate Mito- uter Membrane Permeabilization (MOMP), resulting se of cytochrome c, Smac/DIABLO and Omi/HtrA2 and caspase activation. The Bcl-2 family includes pro- and tic proteins [10]. Anti-apoptotic proteins such as Bcl-2 hibit the function of pro-apoptotic proteins such as Bax 2 family members contain conserved domains (the Bcl- domains named BH1 to BH4), and these domains are r the pro- or anti-apoptotic function of the protein. An ubgroup of pro-apoptotic Bcl-2 members is the ‘BH3- ns, so named because they only have a BH3 domain. nly’ proteins (such as Bik, Bid, Bim, Bad, Puma) have a such as cyto Besides been descri tosis and py been repor ROS followi translocase the cytosol [9]. Finally, cell death, a machinery, been shown activity, we either cell s to the mito Therefor ulation of the interpl dependent 2. Viral co Eliminat ancestral d ing host ce Bcl-2 members (Bax and Bak) promote the release into the cytosol of ion. The pro-apoptotic function of Bax and Bak is antagonized by the it apoptosis of infected cells. tic function by either activating the pro-apoptoticmem- nd Bak) or inhibiting the anti-apoptotic members (such l-XL). The mechanism by which the pro-apoptotic Bcl- embers induce MOMP remains controversial [11]. One odel focuses on the rupture of the outer mitochondrial as a consequence of mitochondrial matrix swelling fol- opening of the permeability transition pore (PTP), a re composed, at least, by the channel VDAC, the ade- tide translocator ANT and cyclophilin D [12]. According model, pro-apoptotic Bcl-2 proteins such as Bax or Bak cificMOMP through the formationof channels or pores, e selective release of proteins that are soluble in the IMS, n cellular defense against microbial infection. Semin chrome c [13]. apoptosis, a number of other cell death pathways have bed, that include autophagic cell death, necrosis, pyrop- ronecrosis (see [14,15] for reviews). Mitochondria have ted to play a role in necrosis through the production of ng disruption of the association between the ADP–ATP (ANT) with cyclophilin D, or through the release into of caspase-independent cell death effectors such as AIF mitochondria also play an important role in autophagic s this organelle is commonly a target of the autophagic in a process that has been termedmitophagy [16]. It has that defective mitochondria, with impaired metabolic re targeted by the mitophagy pathways, resulting in urvival or cell death, dependingon thedegreeof damage chondrial network. e, mitochondria appear to play a central role in the reg- several cell death pathways. The next sections detail ay between microbial infections and mitochondria- cell death pathways. ntrol of mitochondrial apoptosis ion of infected cells throughapoptosis is oneof themost efense mechanisms against infection, hence neutraliz- ll apoptosis represents a critical step for a number of Please cit ria in Immunol ARTICLE IN PRESSG ModelYSMIM-717; No.of Pages10 D. Arnoult et al. / Seminars in Immunology xxx (2009) xxx–xxx 3 viruses. Throughout the process of pathogen–host co-evolution, viruses have therefore acquired distinct strategies to neutralize immunity in infected hosts and they have developed the capability of inhibiting host cell apoptosis. Conversely, some virusesmay take advantage o of infectedc cells of the Several p the host re In addition are also spe host protein apoptosis c anti-apopto similarity t Bcl-2protei apoptosis t lators (3) t trigger MO pro-apopto 2.1. Viral in 2.1.1. Viral B Topreve replication, mimic the a Thefirst adenovirus 2 share a lim and BH3 do large fractio apoptosisd also apopto prevent apo sequesterin and Bak, sim Another protein tha [19]. BHRF1 sis like Bcl- vBcl-2s wit family such 68 M11 and 8 (HHV-8), saimiri (HSV Finally, w found in po (A179L) [24 sequence h have been d Other vi they share ence of “BH exert simila instance for [26,27], and anti-apopto membrane the pro-apo murine cyto the protein lated in the and selectiv prevent MO vMIA/Bax in tational analyses, leading to amodel inwhich the structure of vMIA closely resembles that of Bcl-XL [30]. 2.1.2. Other mitochondria-specific anti-apoptotic viral strategies ses ind on, a mple ondr oduc 1]. ther sis is ax a on o tion d cel lly, H o the opto chon ral pr irec atiti addr e org n of ng in tic k HBx, e de mav y, in te ca rovir uma ro-ap depl IV-1 d VD ted and rgete inne itoch PB1 ondr uires opto ]. lly, o alom ) from tocho [45– Indir men h a d How e of i anne port volv e this article in press as: Arnoult D, et al. The role of mitochond (2009), doi:10.1016/j.smim.2009.05.009 f promoting apoptosis, either to induce the breakdown ells thereby favoringviral spreadingor tokill uninfected immune system. roteins encoded by viral genomes are homologues of gulators of apoptosis, such as Bcl-2 family members. , several key components of the apoptotic machinery cifically targeted by viral factors with no homology to s. Viral proteins that regulate mitochondria-mediated an be therefore classified into the following subgroups: tic proteins (1) that share sequence and/or structural o anti-apoptotic Bcl-2 family members (so-called viral ns or vBcl-2s) or (2) that inhibitmitochondria-mediated hrough other mechanisms; and pro-apoptotic modu- hat directly insert into mitochondrial membranes to MP or (4) that induce MOMP indirectly by activating tic host proteins. hibitors of apoptosis cl-2 homologues (vBcl-2s) nt apoptosis of the infected cells thereby sustainingviral viruses have evolved a battery of Bcl-2 homologues that nti-apoptotic machinery of host cell. vBcl-2 identifiedwas the19-kDaprotein encodedby the (ADV) E1B gene (E1B-19K) [17].While E1B-19K and Bcl- ited sequence similarity, E1B-19K possesses BH1, BH2 mains as well as a transmembrane domain. Like Bcl-2, a n of E1B-19K is found atmitochondria where it inhibits uringadenoviral infection to sustainviral replicationbut sis inducedby several stimuli [18]. E1B-19K is thought to ptosis in a similar way as Bcl-2, likely by inhibiting and g activator(s) of the pro-apoptotic Bcl-2 proteins Bax ilarly to the “BH3-only” proteins Bim and tBid [10]. vBcl-2 is BHRF1, an Epstein–Barr virus (EBV) encoded t shares sequence and structure homology with Bcl-2 also acts at the mitochondrial level to inhibit apopto- 2 [19]. EBV belongs to the herpesvirus family and other h homologies to Bcl-2 have been described in this virus as theKaposi sarcoma-associated Bcl-2 (KSBcl-2),�HV- HVS ORF16 that were identified in human herpesvirus murine �-herpesvirus 68 (�HV-68) and herpesvirus ), respectively [20–22]. ith the Bcl-2-like anti-apoptotic proteins that are also xviruses (ORFV125) [23], in African Swine Fever Virus ] and again in EBV (BALF1) [25], eight vBcl-2s sharing omologies (especially in the BH domains) with Bcl-2 escribed so far [21]. ral factors are also classified as vBcl-2, not because sequence homologies with Bcl-2 (for instance pres- domains”), but rather because they fold like Bcl-2 and r anti-apoptotic properties [21]. This is the case for the proteins F1L and N1L from vaccinia virus (VACV) protein M11L from myxoma virus (MXV) [104]. These tic proteins are localized in the mitochondrial outer like Bcl-2, and are capable of binding and neutralizing ptotic proteins Bax and Bak [21]. Finally, human and megalovirus (CMV) also expresses vBcl-2-like proteins, vMIA and m38.5, respectively. Both proteins (unre- ir amino acid sequence) are found at the mitochondria ely bind/sequester and inactivate Bax, but not Bak, to MP [28,29]. The structure–function relationship of the teraction has been studied by mutational and compu- Viru anisms infecti the co mitoch ATP pr cells [3 Ano apopto teins B infecti regula infecte Fina but als vent ap a mito 2.2. Vi 2.2.1. D Hep that is of thes sipatio resulti apopto ilar to Walley papillo pholog promo Ret or the h with p to the fromH ANT an associa factors also ta across and m The mitoch F2 acq pro-ap [43,44 Fina enceph (NS4A themi anism 2.2.2. As throug teins. capabl rect m been re way in cellular defense against microbial infection. Semin also inhibit apoptosis in infected cells through mech- ependent from vBcl-2s. For instance, following CMV 2.7-kilobase virally encoded RNA (�2.7) interacts with x I of the mitochondrial respiratory chain, stabilizing ial transmembrane potential (��m) for a continued tion leading to an increase in the viability of infected way for viruses to prevent mitochondria-mediated to inhibit activator(s) of the pro-apoptotic Bcl-2 pro- nd Bak [10]. Recently, two groups have reported that f human B lymphocytes by EBV leads to a down- of Bim expression, thereby reducing the propensity of ls to undergo apoptosis [32,33]. HV-8 not only expresses KSBcl-2 to inhibit apoptosis, mitochondrial protein K15. K15 has been shown to pre- sis by binding to HS1-associated protein X-1 (HAX-1), drial inhibitor of apoptosis [34]. o-apoptotic factors t MOMP inducers s B virus (HBV) expresses the X protein (HBx), a protein essed to themitochondria where it induces aggregation anelles and interacts with VDAC3 to promote the dis- the mitochondrial inner membrane potential (��m), apoptosis [35]. Interestingly, HBx sensitizes cells to illing induced by tumor necrosis factor alpha [36]. Sim- viroporin 2B of poliovirus (PLV), OrfC protein from the rmal sarcoma virus (WDSV) and E1E4 from the human iruses (HPVs) localize to mitochondria, alter their mor- duce a perinuclear redistribution of mitochondria and spase-dependent cell death [37–39]. uses like the human immunodeficiency virus 1 (HIV-1) n T lymphotropic virus 1 (HTLV-1) also express proteins optotic activity. In the case of HIV-1, this contributes etion of CD4+ T lymphocytes. The viral protein R (Vpr) has adirectmitochondrial effect because it interactwith AC, thereby promoting PTP opening, leading to MOMP with ��m loss, release of mitochondrial apoptogenic caspase activation [40,41]. pl3(II) protein fromHTLV1 is d to mitochondria, where it induces a rapid flux of ions r membrane together with swelling, ��m dissipation ondrial fragmentation [42]. -F2 protein from influenza A virus (IAV) inserts into ial outer membrane via its C-terminus and there, PB1- a pore forming activity similar to that displayed by tic Bcl-2 members, such as Bax, thus promoting MOMP ther viral proteins such as VP3 and 2C from the avian yelitis virus (AEV) and the non-structural protein 4A hepatitis C virus (HCV) are also found associated to ndria and promoteMOMP through an unknownmech- 47]. ect MOMP inducers tioned above, Vpr from HIV-1 promotes apoptosis irect interaction with mitochondrial membrane pro- ever, other proteins encoded by the HIV-1 are also nitiating mitochondria-mediated apoptosis in an indi- r. The HIV-1 envelope glycoprotein complex (Env) has ed to induceMOMP through a signal transduction path- ing p53-dependent transactivation of Puma and Bax, Please cit ria i Immunol ARTICLE IN PRESSG ModelYSMIM-717; No.of Pages10 4 D. Arnoult et al. / Seminars in Immunology xxx (2009) xxx–xxx p38 MAP kinase, mTOR and Cdk1 [48,49], whereas the Tat pro- tein triggers apoptosis at least partially through the “BH3-only” Bim [50]. The Nef protein induces lysosomal membrane permeabi- lization leading to cathepsin D release into the cytosol, where it triggers Bax 1 protease mitochondr capable of p Othervir ilar to HIV- participates caspase-8-m (2Apro) and [55]. In add through oth modulation ADVsno E1B-19K, to express E1A both p53-d sensitizes c role for the apoptosis, a 3. Mitocho While o fere with m limited, it an importa pathogens death mach mechanism of infected infected ce pathogen d immune sy Mitocho ing number during infe rial pathoge