Thirumala-Devi Kanneganti

Publications (73)745.1 Total impact

• Article: Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection.

  Christopher Lupfer, Paul G Thomas, Paras K Anand, Peter Vogel, Sandra Milasta, Jennifer Martinez, Gonghua Huang, Maggie Green, Mondira Kundu, Hongbo Chi, Ramnik J Xavier, Douglas R Green, Mohamed Lamkanfi, Charles A Dinarello, Peter C Doherty, Thirumala-Devi Kanneganti
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  ABSTRACT: NOD2 receptor and the cytosolic protein kinase RIPK2 regulate NF-κB and MAP kinase signaling during bacterial infections, but the role of this immune axis during viral infections has not been addressed. We demonstrate that Nod2(-/-) and Ripk2(-/-) mice are hypersusceptible to infection with influenza A virus. Ripk2(-/-) cells exhibited defective autophagy of mitochondria (mitophagy), leading to enhanced mitochondrial production of superoxide and accumulation of damaged mitochondria, which resulted in greater activation of the NLRP3 inflammasome and production of IL-18. RIPK2 regulated mitophagy in a kinase-dependent manner by phosphorylating the mitophagy inducer ULK1. Accordingly, Ulk1(-/-) cells exhibited enhanced mitochondrial production of superoxide and activation of caspase-1. These results demonstrate a role for NOD2-RIPK2 signaling in protection against virally triggered immunopathology by negatively regulating activation of the NLRP3 inflammasome and production of IL-18 via ULK1-dependent mitophagy.
  Nature Immunology 03/2013; · 26.01 Impact Factor
• Article: Murine Borrelia arthritis is highly dependent on ASC and caspase-1, but independent of NLRP3.

  Marije Oosting, Kathrin Buffen, Subbarao Rk Malireddi, Patrick Sturm, Ineke Verschueren, Marije I Koenders, Frank L van de Veerdonk, Jos Wm van der Meer, Mihai G Netea, Thirumala-Devi Kanneganti, Leo Ab Joosten
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  ABSTRACT: INTRODUCTION: The protein platform called the Nod-Like-Receptor-family member (NLRP)-3 inflammasome needs to be activated to process intracellular caspase-1. Active caspase-1 is able to cleave pro-Interleukin (IL)-1beta, resulting in bioactive IL-1beta. IL-1beta is a potent pro-inflammatory cytokine, and thought to play a key role in the pathogenesis of Lyme arthritis, a common manifestation of Borrelia burgdorferi infection. The precise pathways through which B.burgdorferi recognition leads to inflammasome activation and processing of IL-1beta in Lyme arthritis has not been elucidated. In the present study, we investigated the contribution of several pattern recognition receptors and inflammasome components in a novel murine model of Lyme arthritis. METHODS: Lyme arthritis was elicited by live B.burgdorferi, injected intraarticularly in knee joints of mice. To identify the relevant pathway components, the model was applied to wild-type, NLRP3-/-, ASC-/-, caspase-1-/-, NOD1-/-, NOD2-/-, and RICK-/- mice. As a control, TLR2-/-, Myd88-/- and IL-1R-/- mice were used. Peritoneal macrophages and bone marrow-derived macrophages were used for in vitro cytokine production and inflammasome activation studies. Joint inflammation was analyzed in synovial specimens and whole knee joints. Mann-Whitney U tests were used to detect statistical differences. RESULTS: We demonstrate that ASC/caspase-1-driven IL-1beta is crucial for induction of B.burgdorferi-induced murine Lyme arthritis. In addition, we show that B.burgdorferi-induced murine Lyme arthritis is less dependent on NOD1/NOD2/RICK pathways while the TLR2-MyD88 pathway is crucial. CONCLUSIONS: Murine Lyme arthritis is strongly dependent on IL-1 production, and B. burgdorferi induces inflammasome-mediated caspase-1 activation. Next to that, murine Lyme arthritis is ASC and caspase-1-dependent, but NLRP3, NOD1, NOD2, and RICK independent. Also, caspase-1 activation by B. burgdorferi is dependent on TLR2 and MyD88. Based on present results indicating that IL-1 is one of the major mediators in Lyme arthritis, there is a rationale to propose that neutralizing IL-1 activity may also have beneficial effects in chronic Lyme arthritis.
  Arthritis research & therapy 11/2012; 14(6):R247. · 4.27 Impact Factor
• Article: Targeting NLRP6 to enhance immunity against bacterial infections.

  Paras K Anand, Thirumala-Devi Kanneganti
  Future Microbiology 11/2012; 7(11):1239-42. · 3.82 Impact Factor
• Article: Toll or Interleukin-1 Receptor (TIR) Domain-containing Adaptor Inducing Interferon-β (TRIF)-mediated Caspase-11 Protease Production Integrates Toll-like Receptor 4 (TLR4) Protein- and Nlrp3 Inflammasome-mediated Host Defense against Enteropathogens.

  Prajwal Gurung, R K Subbarao Malireddi, Paras K Anand, Dieter Demon, Lieselotte Vande Walle, Zhiping Liu, Peter Vogel, Mohamed Lamkanfi, Thirumala-Devi Kanneganti
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  ABSTRACT: Enteric pathogens represent a major cause of morbidity and mortality worldwide. Toll-like receptor (TLR) and inflammasome signaling are critical for host responses against these pathogens, but how these pathways are integrated remains unclear. Here, we show that TLR4 and the TLR adaptor TRIF are required for inflammasome activation in macrophages infected with the enteric pathogens Escherichia coli and Citrobacter rodentium. In contrast, TLR4 and TRIF were dispensable for Salmonella typhimurium-induced caspase-1 activation. TRIF regulated expression of caspase-11, a caspase-1-related protease that is critical for E. coli- and C. rodentium-induced inflammasome activation, but dispensable for inflammasome activation by S. typhimurium. Thus, TLR4- and TRIF-induced caspase-11 synthesis is critical for noncanonical Nlrp3 inflammasome activation in macrophages infected with enteric pathogens.
  Journal of Biological Chemistry 08/2012; 287(41):34474-83. · 4.77 Impact Factor
• Article: NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens.

  Paras K Anand, R K Subbarao Malireddi, John R Lukens, Peter Vogel, John Bertin, Mohamed Lamkanfi, Thirumala-Devi Kanneganti
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  ABSTRACT: Members of the intracellular nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family contribute to immune responses through activation of nuclear factor-κB (NF-κB), type I interferon and inflammasome signalling. Mice lacking the NLR family member NLRP6 were recently shown to be susceptible to colitis and colorectal tumorigenesis, but the role of NLRP6 in microbial infections and the nature of the inflammatory signalling pathways regulated by NLRP6 remain unclear. Here we show that Nlrp6-deficient mice are highly resistant to infection with the bacterial pathogens Listeria monocytogenes, Salmonella typhimurium and Escherichia coli. Infected Nlrp6-deficient mice had increased numbers of monocytes and neutrophils in circulation, and NLRP6 signalling in both haematopoietic and radioresistant cells contributed to increased susceptibility. Nlrp6 deficiency enhanced activation of mitogen-activated protein kinase (MAPK) and the canonical NF-κB pathway after Toll-like receptor ligation, but not cytosolic NOD1/2 ligation, in vitro. Consequently, infected Nlrp6-deficient cells produced increased levels of NF-κB- and MAPK-dependent cytokines and chemokines. Thus, our results reveal NLRP6 as a negative regulator of inflammatory signalling, and demonstrate a role for this NLR in impeding clearance of both Gram-positive and -negative bacterial pathogens.
  Nature 07/2012; 488(7411):389-93. · 36.28 Impact Factor
• Article: Addendum: defective Dock2 expression in a subset of ASC-deficient mouse lines.

  Sirish K Ippagunta, R K Subbarao Malireddi, Patrick J Shaw, Geoffrey A Neale, Lieselotte Vande Walle, Yoshinori Fukui, Douglas R Green, Mohamed Lamkanfi, Thirumala-Devi Kanneganti
  Nature Immunology 07/2012; 13(7):701-2. · 26.01 Impact Factor
• Article: The role of inflammasome modulation in virulence.

  Christopher R Lupfer, Thirumala-Devi Kanneganti
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  ABSTRACT: Pathogens frequently exist in an immunological balancing act with their host. Pathogens must not only replicate within a host but also transmit effectively between hosts to perpetuate their species. On the other hand, the host seeks to maintain homeostasis by clearing pathogens. The inflammasome is a multi-protein complex that can induce cell death and processes IL-1β and additional proinflammatory substrates. In this review we discuss the pathogen specific modulation of inflammasome activation and the role this plays in virulence and disease pathology.
  Virulence 05/2012; 3(3):262-70. · 2.26 Impact Factor
• Article: The inflammasome: a remote control for metabolic syndrome.

  Mohamed Lamkanfi, Thirumala-Devi Kanneganti
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  ABSTRACT: Humans can be divided into roughly three groups with distinct microbial communities in their gastro-intestinal tract. The microbiota contributes to metabolic activity in the gastro-intestinal tract of the host, but what mechanisms shape the composition of the gut microbiota, and how does a person's 'enterotype' affect metabolic processes in distant organs? Flavell and colleagues shed light on these questions by revealing an important role for inflammasomes in modulating the prevalence of colitogenic species, and by demonstrating that dysbiosis influences susceptibility to non-alcoholic steatohepatitis (NASH) and other manifestations of metabolic syndrome.Cell Research advance online publication 10 April 2012; doi:10.1038/cr.2012.55.
  Cell Research 04/2012; 22(7):1095-8. · 8.19 Impact Factor
• Article: Role of inflammasomes in host defense against Citrobacter rodentium infection.

  Zhiping Liu, Md Hasan Zaki, Peter Vogel, Prajwal Gurung, B Brett Finlay, Wanyin Deng, Mohamed Lamkanfi, Thirumala-Devi Kanneganti
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  ABSTRACT: Citrobacter rodentium is an enteric bacterial pathogen of the mouse intestinal tract that triggers inflammatory responses resembling those of humans infected with enteropathogenic and enterohemorrhagic Escherichia coli. Inflammasome signaling is emerging as a central regulator of inflammatory and host responses to several pathogens, but the in vivo role of inflammasome signaling in host defense against C. rodentium has not been characterized. Here, we show that mice lacking the inflammasome components Nlrp3, Nlrc4, and caspase-1 were hypersusceptible to C. rodentium-induced gastrointestinal inflammation. This was due to defective interleukin (IL)-1β and IL-18 production given that il-1β(-/-) and il-18(-/-) mice also suffered from increased bacterial burdens and exacerbated histopathology. C. rodentium specifically activated the Nlrp3 inflammasome in in vitro-infected macrophages independently of a functional bacterial type III secretion system. Thus, production of IL-1β and IL-18 downstream of the Nlrp3 and Nlrc4 inflammasomes plays a critical role in host defense against enteric infections caused by C. rodentium.
  Journal of Biological Chemistry 03/2012; 287(20):16955-64. · 4.77 Impact Factor
• Article: Inflammasome-derived IL-1β regulates the production of GM-CSF by CD4(+) T cells and γδ T cells.

  John R Lukens, Maggie J Barr, David D Chaplin, Hongbo Chi, Thirumala-Devi Kanneganti
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  ABSTRACT: Recent findings have demonstrated an indispensable role for GM-CSF in the pathogenesis of experimental autoimmune encephalomyelitis. However, the signaling pathways and cell populations that regulate GM-CSF production in vivo remain to be elucidated. Our work demonstrates that IL-1R is required for GM-CSF production after both TCR- and cytokine-induced stimulation of immune cells in vitro. Conventional αβ and γδ T cells were both identified to be potent producers of GM-CSF. Moreover, secretion of GM-CSF was dependent on IL-1R under both IL-12- and IL-23-induced stimulatory conditions. Deficiency in IL-1R conferred significant protection from experimental autoimmune encephalomyelitis, and this correlated with reduced production of GM-CSF and attenuated infiltration of inflammatory cells into the CNS. We also find that GM-CSF production in vivo is not restricted to a defined CD4(+) T cell lineage but is rather heterogeneously expressed in the effector CD4(+) T cell population. In addition, inflammasome-derived IL-1β upstream of IL-1R is a critical regulator of GM-CSF production by T cells during priming, and the adapter protein, MyD88, promotes GM-CSF production in both αβ and γδ T cells. These findings highlight the importance of inflammasome-derived IL-1β and the IL-1R/MyD88 signaling axis in the regulation of GM-CSF production.
  The Journal of Immunology 02/2012; 188(7):3107-15. · 5.79 Impact Factor
• Source

  Available from: Peter Vogel

  Article: Signaling via the kinase p38α programs dendritic cells to drive TH17 differentiation and autoimmune inflammation.

  Gonghua Huang, Yanyan Wang, Peter Vogel, Thirumala-Devi Kanneganti, Kinya Otsu, Hongbo Chi
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  ABSTRACT: Dendritic cells (DCs) bridge innate and adaptive immunity, but how DC-derived signals regulate T cell lineage choices remains unclear. We report here that the mitogen-activated protein kinase p38α programmed DCs to drive the differentiation of the T(H)17 subset of helper T cells. Deletion of p38α in DCs protected mice from T(H)17 cell-mediated autoimmune neuroinflammation, but deletion of p38α in macrophages or T cells did not. We also found that p38α orchestrated the expression of cytokines and costimulatory molecules in DCs and further 'imprinted' signaling via the receptor for interleukin 23 (IL-23R) in responding T cells to promote T(H)17 differentiation. Moreover, p38α was required for tissue-infiltrating DCs to sustain T(H)17 responses. This activity of p38α was conserved in mouse and human DCs and was dynamically regulated by pattern recognition and fungal infection. Our results identify p38α signaling as a central pathway for the integration of instructive signals in DCs for T(H)17 differentiation and inflammation.
  Nature Immunology 02/2012; 13(2):152-61. · 26.01 Impact Factor
• Article: The inflammasome puts obesity in the danger zone.

  Rinke Stienstra, Cees J Tack, Thirumala-Devi Kanneganti, Leo A B Joosten, Mihai G Netea
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  ABSTRACT: Obesity-induced inflammation is an important contributor to the induction of insulin resistance. Recently, the cytokine interleukin-1β (IL-1β) has emerged as a prominent instigator of the proinflammatory response in obesity. Several studies over the last year have subsequently deciphered the molecular mechanisms responsible for IL-1β activation in adipose tissue, liver, and macrophages and demonstrated a central role of the processing enzyme caspase-1 and of the protein complex leading to its activation called the inflammasome. These data suggest that activation of the inflammasome represents a crucial step in the road from obesity to insulin resistance and type 2 diabetes.
  Cell metabolism 01/2012; 15(1):10-8. · 17.35 Impact Factor
• Article: IL-1 family cytokines trigger sterile inflammatory disease.

  John R Lukens, Jordan M Gross, Thirumala-Devi Kanneganti
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  ABSTRACT: Inflammation plays vital roles in protective responses against pathogens and tissue repair, however, improper resolution of inflammatory networks is centrally involved in the pathogenesis of many acute and chronic diseases. Extensive advances have been made in recent years to define the inflammatory processes that are required for pathogen clearance, however, in comparison, less is known about the regulation of inflammation in sterile settings. Over the past decade non-communicable chronic diseases that are potentiated by sterile inflammation have replaced infectious diseases as the major threat to global human health. Thus, improved understanding of the sterile inflammatory process has emerged as one of the most important areas of biomedical investigation during our time. In this review we highlight the central role that interleukin-1 family cytokines play in sterile inflammatory diseases.
  Frontiers in immunology. 01/2012; 3:315.
• Article: Regulation of immune pathways by the NOD-like receptor NLRC5.

  Mohamed Lamkanfi, Thirumala-Devi Kanneganti
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  ABSTRACT: Members of the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family are quickly emerging as critical regulators of innate and adaptive immune responses during microbial infection and autoimmunity. The NLR family member NLRC5 was recently proposed to function as a positive and negative regulator of antiviral immune responses. NLRC5 has also been implicated in regulation of inflammasome signaling and MHC class I transcription. Some of these functions have recently been assessed in NLRC5-deficient mice and immune cells. Here, we summarize and review the newly gained knowledge on the structure, expression profile and putative functions of NLRC5 in regulating immune responses and host defense.
  Immunobiology 01/2012; 217(1):13-6. · 3.20 Impact Factor
• Article: Immunological complications of obesity.

  Thirumala-Devi Kanneganti, Vishwa Deep Dixit
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  ABSTRACT: Current approaches for the treatment of obesity, including diet and lifestyle changes, have not been successful in curtailing the obesity epidemic. The higher incidence of inflammation-associated chronic disease and greater susceptibility to infection in obese people represents a growing health threat. Improved understanding of the immunological processes that regulate obesity may yield new treatments for obesity-associated disorders.
  Nature Immunology 01/2012; 13(8):707-12. · 26.01 Impact Factor
• Article: MiR-155 Induction by Microbes/Microbial Ligands Requires NF-κB-Dependent de novo Protein Synthesis.

  Thomas J Cremer, Kavin Fatehchand, Prexy Shah, Devyn Gillette, Hemal Patel, Rachel L Marsh, Beth Y Besecker, Murugesan V S Rajaram, Estelle Cormet-Boyaka, Thirumala-Devi Kanneganti, Larry S Schlesinger, Jonathan P Butchar, Susheela Tridandapani
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  ABSTRACT: MiR-155 regulates numerous aspects of innate and adaptive immune function. This miR is induced in response to Toll-like receptor ligands, cytokines, and microbial infection. We have previously shown that miR-155 is induced in monocytes/macrophages infected with Francisella tularensis and suppresses expression of the inositol phosphatase SHIP to enhance activation of the PI3K/Akt pathway, which in turn promotes favorable responses for the host. Here we examined how miR-155 expression is regulated during infection. First, our data demonstrate that miR-155 can be induced through soluble factors of bacterial origin and not the host. Second, miR-155 induction is not a direct effect of infection and it requires NF-κB signaling to up-regulate fos/jun transcription factors. Finally, we demonstrate that the requirement for NF-κB-dependent de novo protein synthesis is globally shared by microbial ligands and live bacteria. This study provides new insight into the complex regulation of miR-155 during microbial infection.
  Frontiers in cellular and infection microbiology. 01/2012; 2:73.
• Article: Innate immune pathways in host defense.

  Thirumala-Devi Kanneganti, Mohamed Lamkanfi, Amal O Amer
  Mediators of Inflammation 01/2012; 2012:708972. · 3.26 Impact Factor
• Article: TLR2 and RIP2 pathways mediate autophagy of Listeria monocytogenes via extracellular signal-regulated kinase (ERK) activation.

  Paras K Anand, Stephen W G Tait, Mohamed Lamkanfi, Amal O Amer, Gabriel Nunez, Gilles Pagès, Jacques Pouysségur, Maureen A McGargill, Douglas R Green, Thirumala-Devi Kanneganti
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  ABSTRACT: Listeria monocytogenes is a facultative intracellular pathogen that invades both phagocytic and non-phagocytic cells. Recent studies have shown that L. monocytogenes infection activates the autophagy pathway. However, the innate immune receptors involved and the downstream signaling pathways remain unknown. Here, we show that macrophages deficient in the TLR2 and NOD/RIP2 pathway display defective autophagy induction in response to L. monocytogenes. Inefficient autophagy in Tlr2(-/-) and Nod2(-/-) macrophages led to a defect in bacteria colocalization with the autophagosomal marker GFP-LC3. Consequently, macrophages lacking TLR2 and NOD2 were found to be more susceptible to L. monocytogenes infection, as were the Rip2(-/-) mice. Tlr2(-/-) and Nod2(-/-) cells showed perturbed NF-κB and ERK signaling. However, autophagy against L. monocytogenes was dependent selectively on the ERK pathway. In agreement, wild-type cells treated with a pharmacological inhibitor of ERK or ERK-deficient cells displayed inefficient autophagy activation in response to L. monocytogenes. Accordingly, fewer bacteria were targeted to the autophagosomes and, consequently, higher bacterial growth was observed in cells deficient in the ERK signaling pathway. These findings thus demonstrate that TLR2 and NOD proteins, acting via the downstream ERK pathway, are crucial to autophagy activation and provide a mechanistic link between innate immune receptors and induction of autophagy against cytoplasm-invading microbes, such as L. monocytogenes.
  Journal of Biological Chemistry 12/2011; 286(50):42981-91. · 4.77 Impact Factor
• Article: The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis.

  Md Hasan Zaki, Peter Vogel, R K Subbarao Malireddi, Mathilde Body-Malapel, Paras K Anand, John Bertin, Douglas R Green, Mohamed Lamkanfi, Thirumala-Devi Kanneganti
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  ABSTRACT: NLRP12 is a member of the intracellular Nod-like receptor (NLR) family that has been suggested to downregulate the production of inflammatory cytokines, but its physiological role in regulating inflammation has not been characterized. We analyzed mice deficient in Nlrp12 to study its role in inflammatory diseases such as colitis and colorectal tumorigenesis. We show that Nlrp12-deficient mice are highly susceptible to colon inflammation and tumorigenesis, which is associated with increased production of inflammatory cytokines, chemokines, and tumorigenic factors. Enhanced colon inflammation and colorectal tumor development in Nlrp12-deficient mice are due to a failure to dampen NF-κB and ERK activation in macrophages. These results reveal a critical role for NLRP12 in maintaining intestinal homeostasis and providing protection against colorectal tumorigenesis.
  Cancer cell 11/2011; 20(5):649-60. · 25.29 Impact Factor
• Article: TLR2 and RIP2 pathways mediate autophagy of Listeria monocytogenes via ERK activation

  Paras K. Anand, Stephen W.G. Tait, Mohamed Lamkanfi, Amal O. Amer, Gabriel Nunez, Douglas R. Green, Thirumala-Devi Kanneganti
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  ABSTRACT: Listeria monocytogenes is a facultative intracellular pathogen that invades both phagocytic and non-phagocytic cells. Recent studies have shown that L. monocytogenes infection activates the autophagy pathway. However, the innate immune receptors involved and the downstream signaling pathway remain unknown. Here, we show that macrophages deficient in TLR2 and NOD/RIP2 pathway display defective autophagy induction in response to L. monocytogenes. Inefficient autophagy in Tlr2-/- and Nod2-/- macrophages led to defect in bacteria co-localization with the autophagosomal marker GFP-LC3. Consequently, macrophages lacking TLR2 and NOD2 were found to be more susceptible to L. monocytogenes infection as were the Rip2-/- mice. Tlr2-/- and Nod2-/- cells showed perturbed NF-κB and ERK signaling; however, autophagy against L. monocytogenes was dependent selectively on extracellular signal-regulated protein kinase (ERK) pathway. In agreement, wild-type cells treated with pharmacological inhibitors of ERK or ERK-deficient cells displayed reduced autophagy activation in response to L. monocytogenes. Accordingly, fewer bacteria were targeted to autophagosomes and consequently higher bacterial growth was observed in cells deficient in ERK-signaling pathway. These findings thus demonstrate that TLR2 and NOD proteins, acting via downstream ERK pathway, are crucial to autophagy activation and provide a mechanistic link between innate immune receptors and induction of autophagy against cytoplasm invading microbes such as L. monocytogenes.
  Journal of Biological Chemistry 10/2011; · 4.77 Impact Factor