Host Proteasomal Degradation Generates Amino Acids Essential for Intracellular Bacterial Growth

Price, Christopher; Al-Quadan, Tasneem; Šantić, Marina; Rosenshine, Ilan; Kwaik, Yousef Abu

doi:10.1126/science.1212868

Cited by 199 publications

(339 citation statements)

References 38 publications

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“…Importantly, Ap nutrient acquisition does not involve lysosomal of proteasome degradation; instead, a bacterial serine protease seems to be involved. Recently, it was shown that host proteasomal degradation generates amino acids essential for Legionella pneumophila growth (42). Thus, intracellular pathogens evolved diverse mechanisms to obtain required nutrients for replication.…”

Section: Discussionmentioning

confidence: 99%

Autophagosomes induced by a bacterial Beclin 1 binding protein facilitate obligatory intracellular infection

Niu

Xiong

Yamamoto

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

140

160

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Autophagy, a cytoplasmic catabolic process, plays a critical role in defense against intracellular infection. In turn, evasion or inhibition of autophagy has emerged as an important virulence factor for intracellular pathogens. However, Anaplasma phagocytophilum , the obligatory intracellular bacterium that causes human granulocytic anaplasmosis, replicates in the membrane-bound compartment resembling early autophagosome. Here, we found that Anaplasma translocated substrate 1 (Ats-1), a type IV secretion effector, binds Beclin 1, a subunit of the class III PI3K and Atg14L, and it nucleates autophagosomes with markers of omegasomes, double FYVE-containing protein 1, Atg14L, and LC3. Ats-1 autophagy induction did not activate the starvation signaling pathway of mammalian target of rapamycin. These autophagy proteins were also localized to the Anaplasma inclusion. Ectopically expressed Ats-1 targeted the Anaplasma inclusions and enhanced infection, whereas host cytoplasmic delivery of anti–Ats-1 or Beclin 1 depletion by siRNA suppressed the infection; beclin 1 heterozygous-deficient mice were resistant to Anaplasma infection. Furthermore, Anaplasma growth arrest by the class III PI3K inhibitor 3-methyladenine was alleviated by essential amino acid supplementation. Thus, Anaplasma actively induces autophagy by secreting Ats-1 that hijacks the Beclin 1-Atg14L autophagy initiation pathway likely to acquire host nutrients for its growth.

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Section: Discussionmentioning

confidence: 99%

Autophagosomes induced by a bacterial Beclin 1 binding protein facilitate obligatory intracellular infection

Niu

Xiong

Yamamoto

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

140

160

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“…AnkB is crucial for L. pneumophila to acquire nutrition as it locates to the LCV membrane and recruits K48-linked polyubiquitinated proteins, the degradation of which yields amino acids for the bacteria. 125 Another study showed that AnkB is also modified by Trim21-mediated K11-linked ubiquitination; however, this fails to change its stability. 126 LegU1 and LegAU13 are integrated into the host SCF E3 complex, with the former directly ubiquitinating BAT3, a host co-chaperone of Hsp70 that is implicated in ER stress modulation.…”

Section: Shigella Flexnerimentioning

confidence: 99%

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

Chai

Liu

2016

Cell Mol Immunol

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The ubiquitin system comprises enzymes that are responsible for ubiquitination and deubiquitination, as well as ubiquitin receptors that are capable of recognizing and deciphering the ubiquitin code, which act in coordination to regulate almost all host cellular processes, including host-pathogen interactions. In response to pathogen infection, the host innate immune system launches an array of distinct antimicrobial activities encompassing inflammatory signaling, phagosomal maturation, autophagy and apoptosis, all of which are fine-tuned by the ubiquitin system to eradicate the invading pathogens and to reduce concomitant host damage. By contrast, pathogens have evolved a cohort of exquisite strategies to evade host innate immunity by usurping the ubiquitin system for their own benefits. Here, we present recent advances regarding the ubiquitin system-mediated modulation of host-pathogen interplay, with a specific focus on host innate immune defenses and bacterial pathogen immune evasion.

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“…1). Amino acids also play an important role as nutrients during growth within host cells (14,20,(27)(28)(29).…”

mentioning

confidence: 99%

Growth-related Metabolism of the Carbon Storage Poly-3-hydroxybutyrate in Legionella pneumophila

Gillmaier

Schunder

Kutzner

et al. 2016

Journal of Biological Chemistry

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Legionella pneumophila, the causative agent of Legionnaires disease, has a biphasic life cycle with a switch from a replicative to a transmissive phenotype. During the replicative phase, the bacteria grow within host cells in Legionella-containing vacuoles. During the transmissive phenotype and the postexponential (PE) growth phase, the pathogens express virulence factors, become flagellated, and leave the Legionella-containing vacuoles. Using 13 C labeling experiments, we now show that, under in vitro conditions, serine is mainly metabolized during the replicative phase for the biosynthesis of some amino acids and for energy generation. During the PE phase, these carbon fluxes are reduced, and glucose also serves as an additional carbon substrate to feed the biosynthesis of poly-3-hydroxybuyrate (PHB), an essential carbon source for transmissive L. pneumophila. Whole-cell FTIR analysis and comparative isotopologue profiling further reveal that a putative 3-ketothiolase (Lpp1788) and a PHB polymerase (Lpp0650), but not enzymes of the crotonylCoA pathway (Lpp0931-0933) are involved in PHB metabolism during the PE phase. However, the data also reflect that additional bypassing reactions for PHB synthesis exist in agreement with in vivo competition assays using Acanthamoeba castellannii or human macrophage-like U937 cells as host cells. The data suggest that substrate usage and PHB metabolism are coordinated during the life cycle of the pathogen.

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Host Proteasomal Degradation Generates Amino Acids Essential for Intracellular Bacterial Growth

Cited by 199 publications

References 38 publications

Autophagosomes induced by a bacterial Beclin 1 binding protein facilitate obligatory intracellular infection

Autophagosomes induced by a bacterial Beclin 1 binding protein facilitate obligatory intracellular infection

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

Growth-related Metabolism of the Carbon Storage Poly-3-hydroxybutyrate in Legionella pneumophila

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