TY  - JOUR
ID  - open2113
UR  - https://www.tandfonline.com/doi/abs/10.1080/15548627.2018.1436936?journalCode=kaup20
IS  - 6
A1  - Singh, Nisha
A1  - Kansal, Pallavi
A1  - Ahmad, Zeeshan
A1  - Baid, Navin
A1  - Kushwaha, Hariom
A1  - Khatri, Neeraj
A1  - Kumar, Ashwani
Y1  - 2018/05/10/
N2  - IFNG (interferon gamma)-induced autophagy plays an important role in the elimination of intracellular pathogens, such as Mycobacterium tuberculosis (Mtb). However, the signaling cascade that leads to the increase in autophagy flux in response to IFNG is poorly defined. Here, we demonstrate that HMOX1 (heme oxygenase 1)-generated carbon monoxide (CO) is required for the induction of autophagy and killing of Mtb residing in macrophages in response to immunomodulation by IFNG. Interestingly, IFNG exposure of macrophages induces an increase in intracellular calcium levels that is dependent on HMOX1 generated CO. Chelation of intracellular calcium inhibits IFNG-mediated autophagy and mycobacterial clearance from macrophages. Moreover, we show that IFNG-mediated increase in intracellular calcium leads to activation of the phosphatase calcineurin (PPP3), which dephosphorylates the TFEB (transcription factor EB) to induce autophagy. PPP3-mediated activation and nuclear translocation of TFEB are critical in IFNG-mediated mycobacterial trafficking and survival inside the infected macrophages. These findings establish that IFNG utilizes the PPP3-TFEB signaling axis for inducing autophagy and regulating mycobacterial growth. We believe this signaling axis could act as a therapeutic target for suppression of growth of intracellular pathogens.
PB  - Taylor & Francis
JF  - Autophagy
VL  - 14
KW  - TFEB; autophagy; calcineurin; calcium signaling; carbon monoxide; heme oxygenase-1; interferon-gamma; tuberculosis pathogenesis
SN  - 1554-8635
TI  - Antimycobacterial effect of IFNG (interferon gamma)-induced autophagy depends on HMOX1 (heme oxygenase 1)-mediated increase in intracellular calcium levels and modulation of PPP3/calcineurin-TFEB (transcription factor EB) axis.
SP  - 972
EP  - 991
ER  -