Positive and Negative Regulation of the Master Metabolic Regulator mTORC1 by Two Families of Legionella pneumophila Effectors

Abstract

Summary All pathogens must acquire nutrients from their hosts. The intracellular bacterial pathogen Legionella pneumophila, the etiological agent of Legionnaires’ disease, requires host amino acids for growth within cells. The mechanistic target of rapamycin complex 1 (mTORC1) is an evolutionarily conserved master regulator of host amino acid metabolism. Here we identify two families of translocated L. pneumophila effector proteins that exhibit opposing effects on mTORC1 activity. The Legionella glucosyltransferase (Lgt) effector family activates mTORC1, through inhibition of host translation, whereas the SidE/SdeABC (SidE) effector family acts as mTORC1 inhibitors. We demonstrate that a common activity of both effector families is to inhibit host translation. We propose that the Lgt and SidE families of effectors work in concert to liberate host amino acids for consumption by L. pneumophila.

Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1

“…A second example is the enhancement of mTORC1 signaling activity by the Shigella type-III effector OspB in a manner that depends on IQGAP1, thereby promoting proliferation of host cells as a replicative niche during intracellular infection (Lu et al, 2015). As a third example, during Legionella pneumophila infection, two distinct families of the bacterial effectors can positively or negatively impact mTORC1 signaling activity within host cells as a means of regulating the availability of amino acid pools for the auxotrophic intracellular bacterium (De Leon et al, 2017). As these examples illustrate, mTORC1, as a central sensor and regulator of host cell nutrient availability, would be expected to be an attractive target of pathogens attempting to establish an intracellular niche.…”

Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

“…Various pathogens modulate the induction of translation by mTOR to favor the translation of their mRNAs instead of those of the host, to liberate amino acids or to inhibit cytokine responses [172][173][174][175][176]. For example, T. gondii activates mTORC1 to increase translation of mTOR-sensitive transcripts, including those encoding proteins for mitochondrial biogenesis and function.…”

Regulation of Phosphoribosyl-Linked Serine Ubiquitination by Deubiquitinases DupA and DupB

“…PR ubiquitination has been shown to impair GTP-loading and GTP-hydrolysis activity of Rab GTPases (Qiu et al, 2016) and tubular ER rearrangements and potential fragmentation of ER in order to promote proliferation of bacteria in the LCV (Kotewicz et al, 2017). Recent evidence also shows a role of SidE family effectors in regulating mTORC1 activity through PR ubiquitination of Rag GTPases on the lysosome (De Leon et al, 2017). Moreover, the Legionella effector SidJ has been proposed to act as a deubiquitinase for both conventional and PR-linked ubiquitination ; however, recent findings indicate that SidJ acts as a glutamylase that inhibits SidE enzymes by targeting the catalytic site of the ART domains (Bhogaraju et al, 2019;Black et al, 2019;Gan et al, 2019).…”