PMID- 37594275
OWN - NLM
STAT- MEDLINE
DCOM- 20230915
LR  - 20240427
IS  - 1098-5522 (Electronic)
IS  - 0019-9567 (Print)
IS  - 0019-9567 (Linking)
VI  - 91
IP  - 9
DP  - 2023 Sep 14
TI  - Ehrlichia Notch signaling induction promotes XIAP stability and inhibits 
      apoptosis.
PG  - e0000223
LID - 10.1128/iai.00002-23 [doi]
LID - e00002-23
AB  - Ehrlichia chaffeensis has evolved multiple strategies to evade innate defenses of 
      the mononuclear phagocyte. Recently, we reported the E. chaffeensis tandem repeat 
      protein (TRP)120 effector functions as a Notch ligand mimetic and a ubiquitin 
      ligase that degrades the nuclear tumor suppressor, F-box and WD repeat 
      domain-containing 7, a negative regulator of Notch. The Notch intracellular 
      domain (NICD) is known to inhibit apoptosis primarily by interacting with 
      X-linked inhibitor of apoptosis protein (XIAP) to prevent degradation. In this 
      study, we determined that E. chaffeensis activation of Notch signaling increases 
      XIAP levels, thereby inhibiting apoptosis through both the intrinsic and 
      executioner pathways. Increased NICD and XIAP levels were detected during E. 
      chaffeensis infection and after TRP120 Notch ligand mimetic peptide treatment. 
      Conversely, XIAP levels were reduced in the presence of Notch inhibitor DAPT. 
      Cytoplasmic and nuclear colocalization of NICD and XIAP was observed during 
      infection and a direct interaction was confirmed by co-immunoprecipitation. 
      Procaspase levels increased temporally during infection, consistent with 
      increased XIAP levels; however, knockdown (KD) of XIAP during infection 
      significantly increased apoptosis and Caspase-3, -7, and -9 levels. Furthermore, 
      treatment with SM-164, a second mitochondrial activator of caspases (Smac/DIABLO) 
      antagonist, resulted in decreased procaspase levels and increased caspase 
      activation, induced apoptosis, and significantly decreased infection. In 
      addition, RNAi KD of XIAP also decreased infection and significantly increased 
      apoptosis. Moreover, ectopic expression of TRP120 HECT Ub ligase catalytically 
      defective mutant in HeLa cells decreased NICD and XIAP levels and increased 
      caspase activation compared to HeLa cells with functional HECT Ub ligase 
      catalytic activity (TRP120-WT). This investigation reveals a mechanism whereby E. 
      chaffeensis modulates Notch signaling to stabilize XIAP and inhibit apoptosis.
FAU - Patterson, LaNisha L
AU  - Patterson LL
AUID- ORCID: 0000-0003-1839-5429
AD  - Department of Pathology, University of Texas Medical Branch , Galveston, Texas, 
      USA.
FAU - Byerly, Caitlan D
AU  - Byerly CD
AUID- ORCID: 0000-0002-3448-0669
AD  - Department of Pathology, University of Texas Medical Branch , Galveston, Texas, 
      USA.
FAU - Solomon, Regina
AU  - Solomon R
AD  - Department of Pathology, University of Texas Medical Branch , Galveston, Texas, 
      USA.
FAU - Pittner, Nicholas
AU  - Pittner N
AD  - Department of Pathology, University of Texas Medical Branch , Galveston, Texas, 
      USA.
FAU - Bui, Duc Cuong
AU  - Bui DC
AD  - Department of Pathology, University of Texas Medical Branch , Galveston, Texas, 
      USA.
FAU - Patel, Jignesh
AU  - Patel J
AD  - Department of Pathology, University of Texas Medical Branch , Galveston, Texas, 
      USA.
FAU - McBride, Jere W
AU  - McBride JW
AUID- ORCID: 0000-0003-3335-1539
AD  - Department of Pathology, University of Texas Medical Branch , Galveston, Texas, 
      USA.
AD  - Department of Microbiology and Immunology, University of Texas Medical Branch , 
      Galveston, Texas, USA.
AD  - Center for Biodefense and Emerging Infectious Diseases, University of Texas 
      Medical Branch , Galveston, Texas, USA.
AD  - Sealy Institute for Vaccine Sciences, University of Texas Medical Branch , 
      Galveston, Texas, USA.
AD  - Institute for Human Infections and Immunity, University of Texas Medical Branch , 
      Galveston, Texas, USA.
LA  - eng
GR  - T32 AI007526/AI/NIAID NIH HHS/United States
GR  - AI007526/AI/NIAID NIH HHS/United States
GR  - AI152424/AI/NIAID NIH HHS/United States
GR  - AI158422/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20230818
PL  - United States
TA  - Infect Immun
JT  - Infection and immunity
JID - 0246127
RN  - 0 (X-Linked Inhibitor of Apoptosis Protein)
RN  - 0 (Ligands)
RN  - EC 3.4.22.- (Caspases)
RN  - 0 (XIAP protein, human)
SB  - IM
UOF - bioRxiv. 2023 Jan 07;:. PMID: 36711597
MH  - Humans
MH  - X-Linked Inhibitor of Apoptosis Protein/genetics
MH  - HeLa Cells
MH  - Ligands
MH  - Apoptosis
MH  - Caspases
MH  - *Ehrlichia chaffeensis/genetics
MH  - *Ehrlichiosis
PMC - PMC10501217
OTO - NOTNLM
OT  - Ehrlichia chaffeensis
OT  - Notch signaling
OT  - XIAP
OT  - apoptosis
OT  - caspase
COIS- The authors declare no conflict of interest.
EDAT- 2023/08/18 12:42
MHDA- 2023/09/15 06:43
PMCR- 2023/08/18
CRDT- 2023/08/18 09:03
PHST- 2023/09/15 06:43 [medline]
PHST- 2023/08/18 12:42 [pubmed]
PHST- 2023/08/18 09:03 [entrez]
PHST- 2023/08/18 00:00 [pmc-release]
AID - 00002-23 [pii]
AID - iai.00002-23 [pii]
AID - 10.1128/iai.00002-23 [doi]
PST - ppublish
SO  - Infect Immun. 2023 Sep 14;91(9):e0000223. doi: 10.1128/iai.00002-23. Epub 2023 
      Aug 18.