Xu Pinglong's team at Zhejiang University reveals the function and mechanism of blood sugar regulation and antiviral innate immunity Cell Press dialogue scientists

Life Sciences

Life science

On November 15, 2022, Xu Pinglong's laboratory at the Institute of Life Sciences of Zhejiang University published a research paper
titled "AMPK directly phosphorylates TBK1 to integrate glucose sensing into innate immunity" online in the Cell Press journal Molecular Cell.
This study reveals the function and mechanism
of blood glucose level control and antiviral innate immunity.
The physiological phenomenon of rapid decrease in blood glucose level in the very early stage of viral infection and the resulting significant activation of AMPK, the core molecule of glycolipid metabolism, was reported, and the natural immune key kinase TBK1 was identified as the direct substrate of AMPK, and the precise mechanism
of the body's dual perception of nucleic acid and glucose molecular levels through the AMPK-TBK1 signaling axis was revealed 。 These new findings demonstrate the intrinsic molecular connection between glycolipid metabolism and natural immune response, which is an important expansion of research in the field of immunometabolism, and also provides a theoretical and experimental basis
for targeting AMPK to control immune response.

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Glucose is the main source of energy for organisms to maintain normal life activities, and it is also an important medium
for body cells to perceive environmental changes.
The protein kinase AMPK is the body's main energy and glucose abundance sensor, which recognizes and modifies specific amino acid sequence patterns, phosphorylates a variety of substrate molecules, and thus regulates the body's carbohydrates, lipids and other metabolic processes, maintaining cellular energy, oxidation levels and nutrient balance
.
Nucleic acid natural immune recognition is an important mechanism for the body to perceive microbial invasion and self-tissue damage, which is essential
for host cells to resist foreign microbial infection and maintain homeostasis.
Recent studies have also found that hyperglycemia and diabetes are closely
related to susceptibility to microbial infections, including coronavirus infection.
But little is known about how the body integrates information about glucose levels and thus regulates host immunity
.
Through an interesting phenomenon found in rodent virus models, that is, different types of viral infections can induce rapid and sharp drops in blood glucose levels in a variety of rodents, the authors found that AMPK in tissues and organs was significantly activated, and subsequent studies proved that AMPK can directly recognize the classical substrate motif of TBK1 protein and efficiently phosphorylate TBK1 511 serine, thereby promoting TBK1 activation and TBK1-IRF3 interaction.
and the assembly of MAVS and STING signaling complexes, which significantly promote innate immune responses and antiviral host defenses
.
Phenotypically, targeted knock-in mice and cells with TBK1 gene that reduced glucose levels, activated AMPK, or mimickated AMPK-modified showed a hypersensitive innate immune response, while inhibition or blocking of AMPK-TBK1 signaling led to loss of innate immune recognition and response
to viral infection.

The work was done by Xu Pinglong's laboratory and Lin Shengcai's laboratory at Xiamen University
.
Dr.
Qian Zhang, Dr.
Shengduo Liu and Professor Chensong Zhang are the co-first authors of the paper, and Professor Pinglong Xu is the corresponding author
.
The research work has also received strong support
from collaborators such as Professor Feng Xinhua, Professor Liang Tingbo, Professor Huang Yaowei, etc.
The research is supported
by the Key R&D Program of the Ministry of Science and Technology, the National Jieqing Fund, the National Natural Key Project, and the National Nature Surface Project.

Figure Blood glucose level regulates nucleic acid recognition and infection immune response through AMPK-TBK1 signaling mechanism

Author's interview

The public account of Cell Press specially invited Professor Xu Pinglong to accept an exclusive interview on behalf of the research team, and asked him to further explain
it in detail.

CellPress：

Clinically, patients with hyperglycemia are susceptible to a variety of viruses, and are often accompanied by more severe disease symptoms
.
What important contribution has your work made to unravel blood glucose levels and the mechanisms of viral infections?

Professor Xu Pinglong:

The idea that hyperglycemia is susceptible to multiple viruses, including the novel coronavirus, and has more severe symptoms is based on long-term clinical observations
.
Our study validates this phenomenon in cells and model animals and proposes the succinct molecular mechanism
of AMPK-TBK1.
Interestingly, we were surprised to observe a rapid and dramatic drop in blood glucose levels in the very early stages of rodent virus infection, and thus significantly activated AMPK within tissues, promoting a natural immune response
mediated by TBK1.
The mechanism by which viruses cause drastic changes in blood sugar levels in the body is currently unknown, but the phenomenon is found in a variety of viral and animal species and relies on viral nucleic acids (RNA or DNA).

Whether a similar phenomenon exists in humans, or whether it is simply an evolutionary advantage of rodents, we don't yet have an answer
.

CellPress：

Is there a direct physiological connection between the body's blood glucose levels and AMPK, the cell's primary energy receptor?

Professor Xu Pinglong:

AMPK has long been thought to be an energy receptor in cells, sensing the abundance of AMP molecules and activating
them.
However, in recent years, a series of studies in Academician Lin Shengcai's laboratory have proposed an innovative theory
that AMPK directly senses glucose abundance.
By examining primary or cultured cells infected with the virus, we found that AMPK activation significantly predates changes at the AMP molecular level, clearly supporting the idea that
AMPK senses glucose levels.
Notably, we found a sharp decrease in blood glucose concentration in the early stages of viral infection, and significant activation
of AMPK in tissues was also identified by the in vivo detection system for AMPK activity and analysis of organ tissues.
Therefore, our study supports the important physiological link
of blood glucose concentration - intratissue glucose concentration - AMPK activation.

CellPress：

Is AMPK activation a key determinant of antiviral natural immune activation?

Professor Xu Pinglong:

The activation of the antiviral innate immune response, in addition to the activation of nucleic acid recognition receptors and pathways, is also subject to very complex and precise regulation
.
We were surprised to find that cells or tissues lacking AMPK activation had almost complete resting of nucleic acid immune recognition pathways
.
Conversely, various conditions that activate AMPK strongly promote cGAS-STING and RLR-MAVS-mediated antiviral innate immune responses
.
At the same time, TBK1 point-in-place knock-in mice that mimicked AMPK-modified showed hypersensitivity to natural immune response and virus resistance
.
Therefore, we believe that the perception of glucose abundance and the activation of AMPK are determinants of antiviral innate immune activation
.
On the other hand, our body's important natural immune response mechanism is controlled
by both blood sugar levels and tissue damage, including viral invasion.
This innovative concept is important implications
for understanding the innate immune response.

CellPress：

Does eating habits or long-term use of AMPK agonists, such as metformin or aspirin, help fight viral infections?

Professor Xu Pinglong:

Calorie restriction, exercise, hormones, and many natural products used in traditional herbal medicine, such as metformin and salicylic acid, are known to activate AMPK
.
In addition, the therapeutic potential of targeted AMPK in a variety of disease areas has begun to be recognized, including metabolic diseases, cancer, neuromuscular diseases, chronic kidney disease, pain and aging
.
We believe that activating AMPK through diet and drugs helps to fight viral infections
at a certain range and disease stage by enhancing the body's natural immunity against viruses.
On the other hand, an excessively strong or prolonged natural immune response can also lead to immune damage
to body tissues.
It is also important to note that despite considerable progress, which diseases AMPK agonists are best suited to treat and what potential side effects they have are still being studied
.

CellPress：

What is the scientific significance of identifying TBK1 as a direct substrate for AMPK?

Professor Xu Pinglong:

Activation of AMPK leads to phosphorylation of more than 100 proteins in different metabolic pathways in the body, in which phosphorylation modification of a large number of key metabolic regulatory proteins and metabolic enzymes regulates the metabolism of lipids, cholesterol, carbohydrates and amino acids, as well as mitochondrial function, autophagy and cell growth
.
For example, AMPK can reduce the synthesis and storage of fatty acids and cholesterol, and promote fatty acid oxidation; Improves mitochondrial activity and promotes mitochondrial biogenesis; Increases glucose uptake and promotes glycolysis, inhibits gluconeogenesis
.
TBK1 is a key kinase
for the innate immune response initiated by TLR, RLR and cGAS.
Therefore, the identification of TBK1 as the direct substrate of AMPK greatly improves the understanding of the function and mechanism of AMPK, and expands a new direction
for the new academic field of immunometabolism.
On the other hand, recognizing the important regulation of TBK1 activity by AMPK-mediated information flow also provides new insights
for understanding the innate immune response.

CellPress：

Will your next step revolve around the cells' dual perception of nucleic acids and glucose?

Professor Xu Pinglong:

Yes, this is an interesting direction
that our lab hopes to expand.
Glucose is the body's main energy carrier and information medium, and nucleic acid sensing is an important way for the body to identify damage
.
Therefore, the dual perception of nucleic acids and glucose is a key way
to maintain and regulate metabolic and immune balance in multiple organs.
We are very interested in its regulatory functions in tumor immunity and infectious immunity, and hope to understand how dual perception is coupled or dissolved by triggered molecular cellular mechanisms in the physiological and pathological states of specific organs, understand the precise regulation of metabolism on innate immunity, and hope to develop drugs that regulate directionally
.

About the author

Xu Pinglong

professor

Xu Pinglong is a professor
at the Institute of Life Sciences, Zhejiang University.
He has been engaged in the research of the signaling mechanism, regulation and physiological and pathological functions of nucleic acid natural immune recognition for a long time, discovered the biological functions of nucleic acid recognition, such as protein synthesis, protein liquid phase separation, mitochondrial dynamics, cell differentiation, etc.
, identified the non-classical cGAS-STING-PERK signaling pathway, and put forward academic theories
to control the immune response of nucleic acid recognition, such as proto-oncogene, blood glucose concentration, nutritional microenvironment, and phase separation 。 The research progress has been published by the corresponding author in Nature Cell Biology (2022, 2019, 2017), Molecular Cell (2022, 2021, 2020, 2014), Cell Host & Microbe, Genes & Development and other well-known academic journals, and has been published by international experts in Nature Cell for 10 consecutive times Biology and Molecular Cell write articles or highlight stories
in well-known journals such as Cancer Discovery, Science Signaling, and Cancer Research.
He has won the National Science Foundation for Outstanding Young Scholars, the National Natural Science Foundation of China Key Project, etc.
, and won the Wu Rui Memorial Foundation-Gu Xiaocheng Lecture Award, the Promag Cell Biology Innovation Award, the Youbo Tutor of Zhejiang University (2018, 2019, 2020), and the Qiushi Distinguished Professor of Zhejiang University
.

Zhang Qian, a postdoctoral fellow at Zhejiang University Student Research Institute, studied under Professor Xu Pinglong and engaged in the research
of microenvironment regulation of nucleic acid natural immunity.

Liu Shengduo, a postdoctoral fellow at Zhejiang University Student Research Institute, studied under Professor Xu Pinglong and engaged in the research
of nervous system function and regulatory mechanism of nucleic acid innate immunity.

Zhang Chensong, a professor at Xiamen University Academy of Sciences, has made outstanding contributions
to the research of AMPK activation mechanism.

Relevant paper information

The paper was originally published in Molecular Cell, a journal owned by CellPress Cell Press.