restriction of intracellular bacterial replication through induction of efficient antibacterial autoph- agy (Zheng et al., 2009). The autophagy receptor NDP52 can also target distinct compartments in cells infected with Salmonella, and is required for autophagy activation (Cemma et al., 2011). These data suggest that xenophagy is required for effi- cient targeting and killing of cytosolic pathogens. The post-translational modification (ubiquitination) of intracellular pathogens and the roles of cargo re- ceptors will be discussed in detail in the latter part of this review. Cross-talk of autophagy with innate immune signaling pathways Apart from its initial description, which is that autophagy is a response to amino acid deprivation, to recycle cytoplasmic constituents and synthesize energy for cell survival under stressful/starved conditions, autophagy is also being recognized as an innate immune process that is activated upon recognition of microbial infection (Brodsky and Medzhitov, 2009; Shahnazari and Brumell, 2011). Bacteria and viruses possess molecules termed ‘pathogen associated molecular patterns’ (PAMPs) that bind to pattern-recognition receptors such as toll-like receptors (TLRs) on innate immune cells. Ligation of TLRs with PAMPs is known to activate innate immune cells and subsequently facilitate adaptive immune responses. So far, 10 TLRs in humans and 12 in mice have been identified. On the basis of subcellular localization, TLRs can be divided into extracellular and intracellular receptors: TLR1, 2, 4, 5, 6, and 10 are located on the cell surface. In contrast, TLR3, 7, 8, and 9 are expressed in intracellular endosomal/lysosomal compartments and the endoplasmic reticulum (Manavalan et al., 2011). Bacterial PAMPs are recognized by five TLRs in humans: lipopolysaccharide (LPS) is the main ligand of Gram-negative bacteria for TLR4; lipotechoic acid and diacylated lipopeptides are sensed by TLR2/6; triacylated lipopeptides are sensed by TLR2/1; CpG motifs are sensed by TLR9; and flagellin is sensed by TLR5 (Takeuchi and Akira, 2010). Interestingly, stimulation of TLR2, 4, and 7 with their ligands can stimulate autophagy, which functions to eliminate intracellular mycobacteria (Xu et al., 2007; Shi and Kehrl, 2008; Delgado and Deretic, 2009; Shin et al., 2010b). Thus, TLR responses, which are well-known immune-activating signals, can also directly activate autophagy resulting in killing of invading bacteria. In TLR signaling, several TIR domain-containing adaptor molecules, such as MyD88, TIRAP, and Autophagy in infectious diseases 101 TRIF, lie downstream of TLR and deliver activation signals. (Takeda and Akira, 2004). Upon stimulation of TLR4 with LPS, MyD88, TRIF, and tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6), associate with ubiquitinated autophagy-related pro- tein (Atg)6/Beclin-1, which results in activation of autophagy (Shi and Kehrl, 2010). The roles of further downstream signaling molecules of the TLR signaling pathway in the regulation of autophagy remain to be determined. Among them, the role of nuclear factor (NF)-κB, an important downstream mediator of TLR signaling (Takeda and Akira, 2004), in autophagy is still being debated. Although the NF-κB signaling pathway inhibits the autophagy pathways in tumor cells (Djavaheri-Mergny et al., 2006) and keratinocytes (Lee et al., 2011), this has not been confirmed in primary innate cells, such as macrophages or dendritic cells. Mitogen-activated protein kinase signaling pathways may play a role in autophagy, since they are important in the activation of innate immune signaling during bacterial infection (Jo et al., 2007). The stress-activated signaling molecule, c-Jun N-terminal protein kinase 1 (JNK1), pathway has been known to activate starvation- or ceramide-induced autophagy through Bcl-2 phos- phorylation and subsequent dissociation of Bcl-2 from Beclin-1 (Wei et al., 2008; Pattingre et al., 2009). More comprehensive data are necessary to gain a complete understanding of the roles and regulatory mechanisms of signaling modules in antibacterial autophagic activation. Stimulation of other pattern recognition receptors, including the cytosolic receptor NOD2, regulates autophagy. NOD2 receptor recognition by mura- myldipeptide induces autophagy in dendritic cells through receptor-interacting serine-threonine kinase- 2, ATG5, ATG7 and ATG16L1 (Cooney et al., 2010). Notably, NOD2-induced autophagy activation is required for both direct antimicrobial activities and antigen presentation to T cells via MHC class II antigen to induce adequate CD4+ T cell responses (Cooney et al., 2010). These studies suggest that specific PAMP recognition through membrane and cytosolic innate receptors can regulate innate and adaptive immune responses through autophagy activation. Immune effectors and autophagy regulation: cytokines, IRG proteins (p47 GTPases), and cathelicidins Numerous cytokines and chemokines, such as interleukin (IL)-12, IL-23, IL-17, interferon (IFN)-α, IFN-β, IFN-γ, IL-10, IL-27, IL-6, TNF, lymphotoxin, and IL-1 family cytokines, are produced by innate