SLAM is a microbial sensor that regulates bacterial phagosome functions in macrophages

Berger, Scott B.; Romero, Xavier; Ma, Chunyan; Wang, Guoxing; Faubion, William A.; Liao, Guojun; Compeer, Ewoud B.; Keszei, Márton; Rameh, Lucia E.; Wang, Ninghai; Boes, Marianne; Regueiro, José R.; Reinecker, Hans Christian; Terhorst, Cox

doi:10.1038/ni.1931

Cited by 150 publications

(218 citation statements)

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“…60 Loss of SLAM in macrophages decreased the activity of the cell membrane nicotinamide adenine dinucleotide phosphate oxidase NOX2 complex, one of the key mechanisms by which phagocytes kill bacteria. 60 IP 3 R. IP 3 R is a membrane glycoprotein complex acting as Ca 2 þ channel, activated by IP3. In addition to apoptosis, the IP 3 R also regulates autophagy.…”

Section: Slammentioning

confidence: 99%

The Beclin 1 network regulates autophagy and apoptosis

et al. 2011

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Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP 3 R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy. In contrast, the BH3 domain of Beclin 1 is bound to, and inhibited by Bcl-2 or Bcl-XL. This interaction can be disrupted by phosphorylation of Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk between apoptosis and autophagy. Beclin 1 dysfunction has been implicated in many disorders, including cancer and neurodegeneration. Here, we summarize new findings regarding the organization and function of the Beclin 1 network in cellular homeostasis, focusing on the cross-regulation between apoptosis and autophagy. Cell Death and Differentiation (2011) 18, 571-580; doi:10.1038/cdd.2010 published online 11 February 2011 Autophagy is an essential process that consists of selective degradation of cellular components. There are at least three different types of autophagy described and possibly more. These autophagy types include macroautophagy (hereafter referred to as autophagy), microautophagy and chaperonemediated autophagy. 1 The initial step of autophagy is the surrounding and sequestering of cytoplasmic organelles and proteins within an isolation membrane (phagophore). Potential sources for the membrane to generate the phagophore include the Golgi complex, endosomes, the endoplasmic reticulum (ER), mitochondria and the plasma membrane. 2 The nascent membranes are fused at their edges to form double-membrane vesicles, called autophagosomes. Autophagosomes undergo a stepwise maturation process, including fusion with acidified endosomal and/or lysosomal vesicles, eventually leading to the delivery of cytoplasmic contents to lysosomal components, where they fuse, then degrade and are recycled (Figure 1a). The process of mammalian autophagy is divided into six principal steps: initiation (Figure 1b It has been well demonstrated that autophagy depends on Atg5/Atg7, is associated with microtubule-associated protein light chain 3 (LC3) truncation and lipidation, and may originate directly from the ER membrane and other membrane organelles. Furthermore, recent study has identified a Atg5/Atg7-independent pathway of autophagy. 3 This pathway of autophagy was not associated with LC3 processing but appeared to involve autophagosome formation from late endosomes and the trans-Golgi. 3 Atg7-independent autophagy had been implicated in mitochondrial clearance from reticulocytes. 4 The exact molecular basis of Atg5/Atg7-independent autophagy remains to be elucidated. Interestingly, Beclin 1 is required for Atg5/Atg7-dependent and -independent autophagy. 3 However, the presence of Beclin 1-indep...

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Section: Slammentioning

confidence: 99%

The Beclin 1 network regulates autophagy and apoptosis

et al. 2011

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“…Macrophages and neutrophils generate ROS after detection of pathogen-associated molecular patterns (PAMPs) through the NADPH oxidase complex, whereas RNS is produced by inducible nitric oxide synthase (iNOS), which generates NO• through the conversion of L-arginine and oxygen (1)(2)(3).…”

mentioning

confidence: 99%

Direct measurement of oxidative and nitrosative stress dynamics in Salmonella inside macrophages

Heijden

Bosman

Reynolds

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Many significant bacterial pathogens have evolved virulence mechanisms to evade degradation and exposure to reactive oxygen (ROS) and reactive nitrogen species (RNS), allowing them to survive and replicate inside their hosts. Due to the highly reactive and short-lived nature of ROS and RNS, combined with limitations of conventional detection agents, the mechanisms underlying these evasion strategies remain poorly understood. In this study, we describe a system that uses redox-sensitive GFP to nondisruptively measure real-time fluctuations in the intrabacterial redox environment. Using this system coupled with high-throughput microscopy, we report the intrabacterial redox dynamics of Salmonella enterica Typhimurium (S. Typhimurium) residing inside macrophages. We found that the bacterial SPI-2 type III secretion system is required for ROS evasion strategies and this evasion relies on an intact Salmonella-containing vacuole (SCV) within which the bacteria reside during infection. Additionally, we found that cytosolic bacteria that escape the SCV experience increased redox stress in human and murine macrophages. These results highlight the existence of specialized evasion strategies used by intracellular pathogens that either reside inside a vacuole or "escape" into the cytosol. Taken together, the use of redox-sensitive GFP inside Salmonella significantly advances our understanding of ROS and RNS evasion strategies during infection. This technology can also be applied to measuring bacterial oxidative and nitrosative stress dynamics under different conditions in a wide variety of bacteria.oxidative stress | reactive oxygen species | Salmonella | bacterial pathogenesis | redox-sensitive GFP

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“…Interestingly, many previously reported Beclin 1-interacting proteins were not detected in these purifications, indicating that those interactions are rather unstable, transient or specific for certain conditions [88]. These associated proteins include Bcl-2 homologs [93][94][95][96][97], Ambra1 [98], nPIST [99], VMP1 [100], Rab5 [101], FYVE-CENT [102], estrogen receptor [103], MyD88/TRIF [104], SLAM [105], Survivin [106], PINK1 [107], and HMGB1 [108][109][110]. Additionally Bif1 and IP3Rs have been reported to indirectly bind Beclin 1 via UVRAG and Bcl-2, respectively [111,112].…”

Section: The Pi3k Class III Complexmentioning

confidence: 99%