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

Abstract

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.

Neuronal-targeted TFEB rescues dysfunction of the autophagy-lysosomal pathway and alleviates ischemic injury in permanent cerebral ischemia

“…This finding suggested that TFEB translocated to the nucleus at the early stage of ischemia through the activation of PPP3/ calcineurin. In fact, PPP3/calcineurin activation has been reported to respond to ischemic conditions in OGD-induced neuronal death [41],[] and PPP3/calcineurin-dependent TFEB nuclear translocation [42] is involved in the induction of autophagy [43,44]. The data here confirmed the potential of PPP3/calcineurin to regulate TFEB function after ischemic stroke.…”

Host heme oxygenase‐1: Friend or foe in tackling pathogens?

“…Nuclear TFEB induces lysosomal biogenesis and autophagic flux, and clearance of intracellular Mtb. The HMOX1‐dependent induction of autophagy is also observed in Mtb‐infected mice . This pathway is summarized in Fig.…”

“…These findings indicate that HMOX1 plays a role in protection from mycobacterial infection. In an effort to delineate the molecular mechanism of HMOX1‐mediated cellular protection, we have demonstrated that HMOX1 is required for IFN‐γ‐induced autophagy . IFN‐γ‐induced autophagy plays a crucial role in the clearance of intracellular Mtb ; however, the mechanism is poorly understood.…”

The Peroxisome Proliferator-Activated Receptor α- Agonist Gemfibrozil Promotes Defense Against Mycobacterium abscessus Infections

“…TFEB is an essential transcription factor for genes involved in autophagy and lysosomal biogenesis [34]. TFEB activation is required for IFNγ-or PPARα-induced autophagy and restriction of the intracellular growth of M. tuberculosis [20,35]. However, the nuclear translocation of TFEB has not been investigated in the context of Mabc infection.…”