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Literature summary extracted from

  • Voss, O.H.; Gillespie, J.J.; Lehman, S.S.; Rennoll, S.A.; Beier-Sexton, M.; Rahman, M.S.; Azad, A.F.
    Risk1, a phosphatidylinositol 3-kinase effector, promotes Rickettsia typhi intracellular survival (2020), mBio, 11, e00820-20 .
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

EC Number Cloned (Comment) Organism
2.7.1.137 gene RT1035, recombinant expression of wild-type and mutant enzymes in HeLa cells Rickettsia typhi

Protein Variants

EC Number Protein Variants Comment Organism
2.7.1.137 H297A site-directed mutagenesis, a kinase dead mutant. Overexpression of Risk1 H297A results in a significant reduction in colocalization with all tested PI sensors. Cells transfected with Risk1 H297A display a significant increase in apoptosis Rickettsia typhi

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.7.1.137 1-([2-[(2-chloropyridin-4-yl)amino]-4'-(cyclopropylmethyl)[4,5'-bipyrimidin]-2'-yl]amino)-2-methylpropan-2-ol Vpsn34-IN1 Rickettsia typhi
2.7.1.137 proteinase K proteinase K treatment of partially purified Rickettsia typhi results in a dose-dependent degradation of Risk1 on the bacterial membrane Rickettsia typhi

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
2.7.1.137 additional information the enzyme is secreted intracellularly in the host cell by Rickettsia typhi. Risk1 is present in both the pellet and supernatant of infected cells, implying that Risk1 is secreted into the host cell cytoplasm. Risk1 and Rab5 or EEA1 colocalization Rickettsia typhi
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Metals/Ions

EC Number Metals/Ions Comment Organism Structure
2.7.1.137 Mg2+ required Rickettsia typhi

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.7.1.137 ATP + 1-phosphatidyl-1D-myo-inositol Rickettsia typhi
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 ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
-
 ?
2.7.1.137 ATP + 1-phosphatidyl-1D-myo-inositol Rickettsia typhi ATCC VR-144
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 ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
-
 ?
2.7.1.137 ATP + 1-phosphatidyl-1D-myo-inositol Rickettsia typhi Wilmington
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 ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
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 ?

Organism

EC Number Organism UniProt Comment Textmining
2.7.1.137 Rickettsia typhi Q68XM2 progressed in Vero 76 cells
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2.7.1.137 Rickettsia typhi ATCC VR-144 Q68XM2 progressed in Vero 76 cells
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2.7.1.137 Rickettsia typhi Wilmington Q68XM2 progressed in Vero 76 cells
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Posttranslational Modification

EC Number Posttranslational Modification Comment Organism
2.7.1.137 additional information proteinase K treatment of partially purified Rickettsia typhi results in a dose-dependent degradation of Risk1 on the bacterial membrane Rickettsia typhi

Source Tissue

EC Number Source Tissue Comment Organism Textmining
2.7.1.137 additional information the enzyme is secreted intracellularly in the host cell by Rickettsia typhi. Risk1 is present in both the pellet and supernatant of infected cells, implying that Risk1 is secreted into the host cell cytoplasm. Risk1 is deposited on the rickettsial cell surface after translocation through the secretion channel and is delivered into the host cell environment during Rickettsia typhi infection. Strong colocalization is observed between wild-type Risk1 and the tagged biosensors for PI(3)P, PI(3,4,5)P3, PI(3,4)P2, and PI(4,5)P2 in host cells Rickettsia typhi
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Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.7.1.137 ATP + 1-phosphatidyl-1D-myo-inositol
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 Rickettsia typhi ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
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 ?
2.7.1.137 ATP + 1-phosphatidyl-1D-myo-inositol
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 Rickettsia typhi ATCC VR-144 ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
-
 ?
2.7.1.137 ATP + 1-phosphatidyl-1D-myo-inositol
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 Rickettsia typhi Wilmington ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
-
 ?
2.7.1.137 additional information wild-type Risk1 binds preferentially to PIs (i.e., phosphatidylinositol [PI], phosphatidylinositol 4-phosphate [PI(4)P], phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], and phosphatidylserine [PS]) over other lipids such as phosphatidylethanolamine (PE), phosphatidylcholine (PC), diacylglycerol (DAG), cholesterol, or sphingomyelin. Class III PI3Ks convert PI to phosphatidylinositol 3-phosphate [PI(3)P] Rickettsia typhi ?
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2.7.1.137 additional information wild-type Risk1 binds preferentially to PIs (i.e., phosphatidylinositol [PI], phosphatidylinositol 4-phosphate [PI(4)P], phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], and phosphatidylserine [PS]) over other lipids such as phosphatidylethanolamine (PE), phosphatidylcholine (PC), diacylglycerol (DAG), cholesterol, or sphingomyelin. Class III PI3Ks convert PI to phosphatidylinositol 3-phosphate [PI(3)P] Rickettsia typhi ATCC VR-144 ?
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-
2.7.1.137 additional information wild-type Risk1 binds preferentially to PIs (i.e., phosphatidylinositol [PI], phosphatidylinositol 4-phosphate [PI(4)P], phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], and phosphatidylserine [PS]) over other lipids such as phosphatidylethanolamine (PE), phosphatidylcholine (PC), diacylglycerol (DAG), cholesterol, or sphingomyelin. Class III PI3Ks convert PI to phosphatidylinositol 3-phosphate [PI(3)P] Rickettsia typhi Wilmington ?
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Subunits

EC Number Subunits Comment Organism
2.7.1.137 ? x * 81000, native enzyme, SDS-PAGE, x * 82000, recombinant codon-optimized enzyme, SDS-PAGE Rickettsia typhi

Synonyms

EC Number Synonyms Comment Organism
2.7.1.137 phosphatidylinositol 3-kinase
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 Rickettsia typhi
2.7.1.137 PI3K
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 Rickettsia typhi
2.7.1.137 Rickettsia intracellular secreted kinase-1
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 Rickettsia typhi
2.7.1.137 Risk1
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 Rickettsia typhi
2.7.1.137 RT0135
-
 Rickettsia typhi

Cofactor

EC Number Cofactor Comment Organism Structure
2.7.1.137 ATP
-
 Rickettsia typhi

General Information

EC Number General Information Comment Organism
2.7.1.137 evolution RT0135 contains conserved residues within the catalytic and activation loops of the diverse PI3/PI4 family effectors Rickettsia typhi
2.7.1.137 malfunction pretreatment of Rickettsia with Risk1-specific antibody for various lengths of time shows that neutralization of Risk1 significantly reduces Rickettsia typhi internalization, which is consequently resulting in an increase in bacterial adherence. In contrast, pretreatment of Rickettsia typhi with an alphaIgG isotype control Ab shows no reduction in bacterial internalization, indicating that the reduction in Rickettsia typhi infectivity is the result of direct inhibition of Risk1 functionality and not due to steric hindrance induced by the Fc portion of the alphaRisk1 Ab. Cells overexpressing wild-type Risk1 have an about 2.5fold higher bacterial burden than cells expressing either vector or Risk1 H297A mutant. Inhibition of PI3K activity negatively affects Rickettsia typhi internalization and the colocalization of Risk1 with Rab5 and EEA. Cells transfected with Risk1 H297A display a significant increase in apoptosis1 Rickettsia typhi
2.7.1.137 metabolism no association between Beclin-1 and Risk1 or Bcl-2 is observed after prolonged Rickettsia typhi infection Rickettsia typhi
2.7.1.137 physiological function Risk1 is a phosphatidylinositol 3-kinase (PI3K) and a secreted effector involved in Rickettsia typhi host cell invasion, a T4SS effector, and the first bacterial secretory kinase with both class I and III PI3K activities. The rickettsial effector phosphatidylinositol 3-kinase (PI3K) has a dual specificity for phosphoinositides. Risk1 is a phosphatidylinositol 3-kinase with class I and III activities critical for Rickettsia typhi invasion. During infection, Risk1 targets the Rab5-EEA1-phosphatidylinositol 3-phosphate [PI(3)P] signaling axis to promote bacterial phagosomal escape. binding to Rab5 requires the kinase activity of Risk1. Subsequently, Rickettsia typhi undergoes ubiquitination and induces host autophagy. Maturation to autolysosomes is subverted to support intracellular growth. Only enzymatically active Risk1 binds the Beclin-1 core complex and contributes to Rickettsia typhi-induced autophagosome formation. Risk1, with dual class I and class III PI3K activities, alters host PI metabolism and consequently subverts intracellular trafficking to facilitate intracellular growth of Rickettsia typhi. Risk1 targets endosomal trafficking and Rickettsia typhi-induced autophagy to promote intracellular growth. Risk1, via its kinase activity, contributes to a nonapoptotic cell rounding phenotype Rickettsia typhi