The ubiquitin ligase parkin mediates resistance to intracellular pathogens

Abstract

Summary Ubiquitin-mediated targeting of intracellular bacteria to the autophagy pathway is a key innate defense mechanism against invading microbes, including the important human pathogen Mycobacterium tuberculosis. However, the ubiquitin ligases responsible for catalyzing ubiquitin chains that surround intracellular bacteria are poorly understood. PARKIN is a ubiquitin ligase with a well-established role in mitophagy, and mutations in the PARKIN gene (Park2) lead to increased susceptibility to Parkinson’s disease. Surprisingly, genetic polymorphisms in the Park2 regulatory region are also associated with increased susceptibility to intracellular bacterial pathogens in humans, including Mycobacterium leprae and Salmonella typhi, but the function of PARKIN in immunity remains unexplored. Here we show that PARKIN plays a role in ubiquitin-mediated autophagy of M. tuberculosis. Both PARKIN-deficient mice and flies are sensitive to various intracellular bacterial infections, suggesting PARKIN plays a conserved role in metazoan innate defense. Moreover, our work reveals an unexpected functional link between mitophagy and infectious disease.

Recruitment of TBK 1 to cytosol‐invading Salmonella induces WIPI 2‐dependent antibacterial autophagy

“…The bacterial ubiquitin coat that develops subsequent to SCV damage comprises another “eat‐me” signal (Perrin et al , 2004). Two E3 ligases, Parkin and LRSAM1, have been suggested to generate the bacterial ubiquitin coat, possibly in response to different bacterial species (Huett et al , 2012; Manzanillo et al , 2013). The ubiquitin “eat‐me” signal is detected by several cargo receptors, of which optineurin and NDP52 provide independent physical links to TBK1.…”

Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins

“…) GKS-independent ubiquitination of PVs could facilitate the translocation of GBPs to PVs in human cells. The coating of intracellular pathogens with ubiquitin is indeed a conserved defense mechanism found in host organisms as diverse as fruit flies and humans (28,50). Specifically, the E3 ligases Parkin and LRSAM1 were found to be required for the ubiquitination of intracellular Mycobacterium tuberculosis and Salmonella enterica in mouse and human cells (50,51).…”

The ubiquitin system: a critical regulator of innate immunity and pathogen–host interactions

“…Recent research partially sheds light on the underlying mechanism: the bacterial ESX-1 T7SS-mediated phagosomal permeabilization allows the cGAS-STING-dependent cytosolic DNA sensor pathway to access extracellular bacterial DNA and then triggers parkinmediated K63-linked ubiquitination surrounding the Mtbcontaining phagosome, which is required for the delivery of bacilli to autophagosomes. [65][66][67] Despite these observations, it is still poorly understood how parkin is recruited and activated at the bacterial niche and which bona fide protein(s) are targeted by parkin, as well as the identity of other E3s responsible for K48-linked ubiquitination. Another well-defined example involves the LRR-harboring RING family E3 ligase LRSAM1, which targets Sa.…”