**6. Receptor proteins required for the restriction of infectious bacterial growth by autophagy**

Autophagy also serves as a cell-autonomous effector mechanism of innate immunity in the cytosol. It does this through restricting bacterial proliferation by separating bacteria from the nutrient-rich cytosol and delivering them into bactericidal autolysosomes. Several examples showing that these types of autophagy are mediated by cytosolic bacteriarecognizing receptor proteins have been recently reported. In *Drosophila melanogaster*, PGRP-LE, a receptor protein for bacterial peptidoglycans, induces autophagy of wild-type but not listeriolysin-deficient *Listeria monocytogenes*, suggesting that this pathway specifically selects cytosolic bacteria for autophagy (Yano et al., 2008). However, it is unknown how PGRP-LE induces the autophagic degradation of *L. monocytogenes* and whether PGRP-LE binds the *D. melanogaster* Atg8 orthologs.

*Salmonella enterica* Typhimurium (*S.* Typhimurium) typically occupies a membrane bound compartment, the Salmonella-containing vacuole (SCV), in host cells. In mammalian cells, *S.* Typhimurium and other bacteria enter the cytosol and are released from SCVs, then become coated with a dense layer of ubiquitin (Perrin et al., 2004) and are delivered to lysosomes via autophagy (Birmingham et al., 2006). It was reported that p62 functions as a receptor protein for delivering such ubiquitin-coated bacteria into autophagosomes (Dupont et al., 2009; Zheng et al., 2009). In addition to p62, two other receptor proteins were identified, NDP52 (Thurston et al., 2009) and Optineurin (Wild et al., 2011), both of which recognize ubiquitin-coated bacteria. NDP52 is recruited by ubiquitin-coated *S.*  Typhimurium and binds both ubiquitin via a zinc-finger domain (residues 420-446) and LC3. Although NDP52 interacts with LC3, it has not been clarified whether NDP52 has an AIM. NDP52 also coordinates a signaling complex including Tank-binding kinase (TBK1), Sintbad and Nap1. *In vitro* binding studies revealed that a SKICH domain (residues 1-127) in NDP52 is required for direct Nap1 binding. Thereby, NDP52 recruits TBK1 to ubiquitin-coated *S.* Typhimurium. The ability of NDP52 to serve as an adaptor for TBK1 also seems to be critical in the cell-autonomous response, but it remains to be determined what role TBK1 plays in association with NDP52. OPTN is another autophagy receptor protein that binds and co-localizes with LC3 via an AIM (178-FVEI-181) and ubiquitin via its ubiquitin binding in ABIN and NEMO (UBAN) domains. The N-terminal region of OPTN (residues 1-127) also interacts with TBK1 (Morton et al., 2008). When TBK1 is recruited into *S.* Typhimurium via OPTN, it becomes activated and phosphorylates OPTN at Ser-177, one residue N-terminal to the OPTN AIM. The phosphorylation of Ser-177 increases the affinity between OPTN and LC3, which is consistent with the previous review showing that acidic residues are preferred at the N-terminal side of the AIM for higher affinity with Atg8 homologs (Noda et al., 2010). Although p62, NDP52 and OPTN target the same bacteria, NDP52 and OPTN localize to microdomains on the surface of ubiquitinated bacteria where p62 does not co-localize (Cemma et al., 2011; Wild et al., 2011). Because these autophagy receptors have their respective ubiquitin-binding domains, the distinct specificities for different ubiquitin chains may result in partitioning of the receptors to different subdomains on the bacterium. However, it is still unknown which type of ubiquitin chains are conjugated to the bacterial surface components.
