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A Distinct Temporal Regulation of Cellular
Bcl-2 Family Proteins Promotes Survival of
HCMV-Infected Monocytes
Donna Collins-McMillen, E.V. Stevenson, M.T. Nogalski, J. Caskey,
G.C.T. Chan, and A.D. Yurochko
Louisiana State University Health – Shreveport, LA
Monocytes as Vehicles for Viral Spread
1. 2.
3.
4.
5.
6.
7.
Monocyte Survival Hurdle
MФmonocyte
Monocyte Survival Hurdle
MФmonocyte 48hpi
apoptotic programming
“default”
Monocyte Survival Hurdle
MФmonocyte 48hpi
“default” apoptotic programming
Anti-viral
pro-apoptotic response
HCMV Engages a Distinct Pro-Survival
Mechanism to Prevent Monocyte
Apoptosis
1) Bi-phasic regulation of Mcl-1 and Bcl-2
2) Distinct & overlapping signaling through
EGFR/integrins
3) Promotes survival at multiple apoptotic checkpoints
• bypasses viability checkpoint at 48 h (stabilizes Mcl-1,
Chan et al., 2010)
• adapts to anti-viral pro-apoptotic response (Bcl-2 up in
response to Bax)
Bi-Phasic Mcl-1/Bcl-2 Shift
Mcl-1 in HCMV-infected monocytes
MФmonocyte 48hpi
Mcl-1 Bcl-2
(1) (1.2)(1.4) (3.9)(1.9)(5.1) (2.0) (6.2))
Bcl-2 in HCMV-infected monocytesChan et al., 2010
Bi-Phasic Mcl-1/Bcl-2 Shift
• Bcl-2 controls late survival in HCMV-infected monocytes
(Mcl-1 early, Chan et al., 2010)
• Mcl-1 and Bcl-2 are both required for early survival in mock-
infected cells
HCMV Signaling Through EGFR/Integrins
Chan et al., 2010
Bcl-2 Combats the Anti-Viral Pro-
Apoptotic Response (Bax Up-Regulation)
MФmonocyte 48hpi
Mcl-1 Bcl-2
(1) (1.4) (1.2)(4) (2.8)(5.6)(3.3)(10.5))
Bcl-2 (but not Mcl-1)
can bind & inactivate
Bax
Bax Expression Drives Bcl-2 Up-Regulation
Bax Depletion Rescues Infected Bcl-2-Defective
Cells From Apoptosis
Acknowledgements
Mentor
Dr. Andrew Yurochko
Dissertation Committee
Dr. Robert Chervenak
Dr. Lindsey Hutt-Fletcher
Dr. Dennis O’Callaghan
Dr. Kelly Tatchell
Dr. Felicia Goodrum (U of AZ)
Funding:
Yurochko Lab
Liesl Milford
Dr. Maciej Nogalski
Dr. Gary Chan
Dr. Emily Stevenson
Dr. Yanjie Li
Stephen Cieply
Dr. Jung Heon Kim
Joshua Caskey
A156077
P30GM110703
Pre-Doctoral Fellowship
14PRE20310027

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IHW 2015 Talk

  • 1. A Distinct Temporal Regulation of Cellular Bcl-2 Family Proteins Promotes Survival of HCMV-Infected Monocytes Donna Collins-McMillen, E.V. Stevenson, M.T. Nogalski, J. Caskey, G.C.T. Chan, and A.D. Yurochko Louisiana State University Health – Shreveport, LA
  • 2. Monocytes as Vehicles for Viral Spread 1. 2. 3. 4. 5. 6. 7.
  • 4. Monocyte Survival Hurdle MФmonocyte 48hpi apoptotic programming “default”
  • 5. Monocyte Survival Hurdle MФmonocyte 48hpi “default” apoptotic programming Anti-viral pro-apoptotic response
  • 6. HCMV Engages a Distinct Pro-Survival Mechanism to Prevent Monocyte Apoptosis 1) Bi-phasic regulation of Mcl-1 and Bcl-2 2) Distinct & overlapping signaling through EGFR/integrins 3) Promotes survival at multiple apoptotic checkpoints • bypasses viability checkpoint at 48 h (stabilizes Mcl-1, Chan et al., 2010) • adapts to anti-viral pro-apoptotic response (Bcl-2 up in response to Bax)
  • 7. Bi-Phasic Mcl-1/Bcl-2 Shift Mcl-1 in HCMV-infected monocytes MФmonocyte 48hpi Mcl-1 Bcl-2 (1) (1.2)(1.4) (3.9)(1.9)(5.1) (2.0) (6.2)) Bcl-2 in HCMV-infected monocytesChan et al., 2010
  • 8. Bi-Phasic Mcl-1/Bcl-2 Shift • Bcl-2 controls late survival in HCMV-infected monocytes (Mcl-1 early, Chan et al., 2010) • Mcl-1 and Bcl-2 are both required for early survival in mock- infected cells
  • 9. HCMV Signaling Through EGFR/Integrins Chan et al., 2010
  • 10. Bcl-2 Combats the Anti-Viral Pro- Apoptotic Response (Bax Up-Regulation) MФmonocyte 48hpi Mcl-1 Bcl-2 (1) (1.4) (1.2)(4) (2.8)(5.6)(3.3)(10.5)) Bcl-2 (but not Mcl-1) can bind & inactivate Bax
  • 11. Bax Expression Drives Bcl-2 Up-Regulation
  • 12. Bax Depletion Rescues Infected Bcl-2-Defective Cells From Apoptosis
  • 13.
  • 14. Acknowledgements Mentor Dr. Andrew Yurochko Dissertation Committee Dr. Robert Chervenak Dr. Lindsey Hutt-Fletcher Dr. Dennis O’Callaghan Dr. Kelly Tatchell Dr. Felicia Goodrum (U of AZ) Funding: Yurochko Lab Liesl Milford Dr. Maciej Nogalski Dr. Gary Chan Dr. Emily Stevenson Dr. Yanjie Li Stephen Cieply Dr. Jung Heon Kim Joshua Caskey A156077 P30GM110703 Pre-Doctoral Fellowship 14PRE20310027