Abstract
Autophagy, a well-established defense mechanism, enables the elimination of intracellular pathogens including Listeria monocytogenes. Host cell recognition results in ubiquitination of L. monocytogenes and interaction with autophagy adaptors p62/SQSTM1 and NDP52, which target bacteria to autophagosomes by binding to microtubule-associated protein 1 light chain 3 (LC3). Although studies have indicated that L. monocytogenes induces autophagy, the significance of this process in the infectious cycle and the mechanisms involved remain poorly understood. Here, we examined the role of the autophagy adaptor optineurin (OPTN), the phosphorylation of which by the TANK binding kinase 1 (TBK1) enhances its affinity for LC3 and promotes autophagosomal degradation, during L. monocytogenes infection. In LC3- and OPTN-depleted host cells, intracellular replicating L. monocytogenes increased, an effect not seen with a mutant lacking the pore-forming toxin listeriolysin O (LLO). LLO induced the production of OPTN. In host cells expressing an inactive TBK1, bacterial replication was also inhibited. Our studies have uncovered an OPTN-dependent pathway in which L. monocytogenes uses LLO to restrict bacterial growth. Hence, manipulation of autophagy by L. monocytogenes, either through induction or evasion, represents a key event in its intracellular life style and could lead to either cytosolic growth or persistence in intracellular vacuolar structures.
Highlights
Listeria monocytogenes is a Gram-positive, ubiquitously distributed, facultative intracellular pathogen that causes listeriosis, a lethal food-borne disease
listeriolysin O (LLO) is a cholesterol-dependent cytolysin (CDC) that inserts into host plasma membranes to form pores, thereby inducing host cell signaling cascades that regulate repair processes such as autophagy [5]
Autophagy adaptors are characterized by the presence of a ubiquitin-binding domain (UBD) that recognizes ubiquitinated cargo, and an light chain 3 (LC3)-interacting region (LIR) that links this cargo to the autophagosomal membrane [16]
Summary
Listeria monocytogenes is a Gram-positive, ubiquitously distributed, facultative intracellular pathogen that causes listeriosis, a lethal food-borne disease. Autophagy is an innate immune system that restricts the replication of many intracellular pathogens, which include Salmonella typhimurium, Mycobacterium tuberculosis, Streptococcus pyogenes and Streptococcus pneumoniae [12,13,14,15] This process requires autophagy adaptors that and selectively recognize intracellular bacteria for their degradation [9]. Autophagy adaptors are characterized by the presence of a ubiquitin-binding domain (UBD) that recognizes ubiquitinated cargo, and an LC3-interacting region (LIR) that links this cargo to the autophagosomal membrane [16] Pathogens such as S. typhimurium and L. monocytogenes have evolved sophisticated strategies to either suppress autophagy, or even prevent recognition and subsequent capture by the autophagic machinery [17,18,19]. Our data demonstrate that OPTN targets Listeria to degradation in an LLO-dependent manner
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