Divergence of Legionella Effectors Reversing Conventional and Unconventional Ubiquitination

Abstract

The intracellular bacterial pathogen Legionella pneumophila employs bacteria-derived effector proteins in a variety of functions to exploit host cellular systems. The ubiquitination machinery constitutes a crucial eukaryotic system for the regulation of numerous cellular processes, and is a representative target for effector-mediated bacterial manipulation. L. pneumophila transports over 300 effector proteins into host cells through its Dot/Icm type IV secretion system. Among these, several effector proteins have been found to function as ubiquitin ligases, including unprecedented enzymes that catalyze ubiquitination through unconventional mechanisms. Recent studies have identified many L. pneumophila effector proteins that can interfere with ubiquitination. These effectors include proteins that are distantly related to the ovarian tumor protein superfamily described as deubiquitinases (DUBs), which regulate important signaling cascades in human cells. Intriguingly, L. pneumophila DUBs are not limited to enzymes that exhibit canonical DUB activity. Some L. pneumophila DUBs can catalyze the cleavage of the unconventional linkage between ubiquitin and substrates. Furthermore, novel mechanisms have been found that adversely affect the function of specific ubiquitin ligases; for instance, effector-mediated posttranslational modifications of ubiquitin ligases result in the inhibition of their activity. In the context of L. pneumophila infection, the existence of enzymes that reverse ubiquitination primarily relates to a fine tuning of biogenesis and remodeling of the Legionella-containing vacuole as a replicative niche. The complexity of the effector arrays reflects sophisticated strategies that bacteria have adopted to adapt their host environment and enable their survival in host cells. This review summarizes the current state of knowledge on the divergent mechanisms of the L. pneumophila effectors that can reverse ubiquitination, which is mediated by other effectors as well as the host ubiquitin machinery.

Interplay between bacterial deubiquitinase and ubiquitin E3 ligase regulates ubiquitin dynamics on Legionella phagosomes

“…A few DUBs have been described in L. pneumophila ( Kitao et al, 2020 ) of which LotA ( Kubori et al, 2018 ) and Ceg23 ( Ma et al, 2020 ) also belong to the OTU superfamily. Furthermore, LotA exhibits preference toward several chain types, including K6-type ( Kubori et al, 2018 ), which is one of the preferred chain types cleaved by Lem27 (see below).…”

“…In addition to ubiquitin ligases, pathogens also employ DUBs to hijack host cellular processes for their benefits ( Wilkinson, 2009 ) and a number of DUBs have been found in L. pneumophila ( Kitao et al, 2020 ). Among these, members of the SidE effector family harbor DUB activity in a domain that encompasses their first 200 residues, which appears to exhibit preference for K63-linked ubiquitin chains ( Sheedlo et al, 2015 ).…”

Bacterial nucleomodulins: A coevolutionary adaptation to the eukaryotic command center

“…While LegAS4 shares histone H3K14 methylation activity with RomA, LegAS4 differs from RomA by targeting and methylating histone H3K4 [ 3 , 14 , 17 ]. LegAS4 is also hypothesized to interact with HP1 in the nucleolus at rDNA promotors, resulting in an activation of rDNA gene expression [ 3 , 172 , 173 ]. By utilizing RomA or LegAS4, L .…”

Evolution and Adaptation of Legionella pneumophila to Manipulate the Ubiquitination Machinery of Its Amoebae and Mammalian Hosts

“…Multiple intracellular pathogens including Salmonella , Mycobacterium , Shigella , Coxiella , Anaplasma , Chlamydia and Legionella manipulate the host ubiquitin pathway to evade host restriction and generate a replicative niche in eukaryotic cells [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. However, amongst these intracellular pathogens, L. pneumophila possesses the most diverse and novel array of mechanisms to manipulate the eukaryotic ubiquitination machinery [ 42 ]. L. pneumophila resides in a diverse array of amoebal hosts, and as such, has evolved with a complex toolbox of effector proteins to adapt and survive in these environmental unicellular hosts [ 43 , 44 , 45 ].…”