Interferon-stimulated gene TDRD7 interacts with AMPK and inhibits its activation to suppress viral replication and pathogenesis, Chakravarty+

Interferon-stimulated gene TDRD7 interacts with AMPK and inhibits its activation to suppress viral replication and pathogenesis (2023)

Sukanya Chakravarty, Gayatri Subramanian, Sonam Popli, Manoj Veleeparambil, Shumin Fan, Ritu Chakravarti, Saurabh Chattopadhyay
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA

Abstract
[Paragraph breaks added]
Many viruses activate cellular autophagy in infected cells to facilitate their replication. Recently, we identified an interferon (IFN)-stimulated gene (ISG) Tudor domain containing 7 (TDRD7), which inhibits viral replication by blocking autophagy pathway.

Here, we present a molecular mechanism for TDRD7 action and its relative contribution to protection against viral pathogenesis. TDRD7 inhibited the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a kinase required for initiating autophagy.

Mechanistically, TDRD7 interacted directly with AMPK in the cytosolic compartment. Domain-mapping analyses revealed C-terminal Tudor domain of TDRD7 interacted with auto-inhibitory domain of AMPK. Deletion of Tudor domains abolished anti-AMPK and antiviral activities of TDRD7.

We evaluated physiological relevance of TDRD7 function against viral replication using newly engineered TDRD7 knockout mice and the derived primary cells. TDRD7 knockout primary cells displayed increased AMPK activation, which led to a higher viral load. Subsequently, TDRD7 knockout mice showed enhanced susceptibility upon intranasal Sendai virus infection. Therefore, our study revealed a new antiviral function of IFN, mediated by TDRD7-AMPK, inhibiting viral replication and pathogenesis.

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[Explain like I'm brain foggy]

AMPK is an important signaling molecule for facilitating cellular responses to energy-related stress. It has several downstream effects, the main one being increased glucose uptake for ATP production. In order to perform this function, AMPK needs to be phosphorlyated (i.e. "activated"), becoming pAMPK.

This group previously identified TDRD7, which is an interferon-stimulated gene (ISG), i.e. a gene that gets upregulated in response to interferon signaling. In this study, TDRD7 was found to inhibit viral replication by preventing phosphorylation of AMPK, which viruses tend to highjack for their own replication purposes.

Overall, this study shows that an interferon stimulated gene is capable of remodeling cellular metabolism via AMPK.

 

The reason I'm interested in this is because it provides one possible explanation for the AMPK-related findings from Tomas et al. 2020 (thread here) and Brown et al. 2018 (thread here) both from the same group. The main takeaway from those findings was that AMPK levels (and general metabolic functioning) seemed normal at baseline, but could not be activated enough (phosphorylated to pAMPK) to cope with increased metabolic demand from muscle use (stimulated muscle contractions).

[Edit: sorry, the Brown et al. paper with stimulation was actually this one from 2015, which doesn't have a thread]

TDRD7 seems to inhibit AMPK activation by preventing formation of a particular "activation complex". The AMPK activators used in the Tomas and Brown studies would be able to bypass that issue by substantially increasing the amount of those complexes, perhaps outpacing the inhibitory effect of TDRD7.

This is all speculation, but would be in line with the previous findings which suggest it is only AMPK activation, not AMPK levels, which are affected in ME/CFS muscle cells and may cause those cells to simply be able to adapt to higher than baseline metabolic demand in activity. Given that the Tomas and Brown findings were in cultured muscle cells, if interferons were involved in any way (and of course that's speculative in itself), it would point to type I interferons, which can be produced in non-immune cells.

 

And, for completely selfish reasons, this might be an explanation for why positive effects from malic acid may be somewhat dependent on also taking stimulants. Stimulants are thought to affect glucose uptake via norepinephrine (though this seems to be contradictory in different types of cells and understudied overall).

But if stimulants allow this AMPK issue to be bypassed somehow at least in muscle cells, it suggests that there is a 2-part deficit in energy metabolism in ME/CFS: one mediated by AMPK, and one mediated downstream at the malate-asparate shuttle which could be relieved by supplementing malate (supported by Rob Wuest's recent findings of reduced SDH activity in post-COVID PEM).

If the second issue is mediated by something like itaconate being produced by non-muscle cells, then it would explain why only activating AMPK would make these muscle cells start functioning like normal--because only the interferon-TDRD7-AMPK issue would continue in isolated muscle cells.

And would also explain why malic acid might do nothing for people who do not tolerate stimulants--no use fixing a downstream problem if another upstream problem persists.

Of course, could be many other potential explanations. This is just one possible way of putting the puzzle pieces together.