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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNature spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase that plays a vital role in both innate and adaptive immunity
.
However, the key molecular mechanisms that regulate SYK activity are poorly understood
.
On August 6, 2021, the Gao Chengjiang team of Shandong University published an online research paper titled "TRIM31 facilitates K27-linked polyubiquitination of SYK to regulate antifungal immunity" in Signal Transduction and Targeted Therapy (IF=18.
19).
This research combines E3 ligase TRIM31 was identified as a key regulator of SYK activation
.
The study found that TRIM31 interacts with SYK and catalyzes the polyubiquitination of Lys375 of SYK and K27 of Lys517
.
This K27-linked polyubiquitination of SYK promotes its plasma membrane translocation and binding to the C-type lectin receptor (CLR), and prevents the interaction with the phosphatase SHP-1
.
Therefore, the lack of Trim31 in bone marrow-derived dendritic cells (BMDC) and macrophages (BMDM) inhibits SYK-mediated signal transduction and inhibits pro-inflammatory cytokines and chemokines against the fungal pathogen Candida albicans infection Secretion
.
Trim31-/- mice are also more sensitive to systemic Candida albicans infection than Trim31+/+ mice, and show reduced Th1 and Th17 responses
.
Overall, this study revealed the key role of TRIM31-mediated K27-linked polyubiquitination on SYK activation and emphasized the importance of TRIM31 in anti-Candida albicans immunity
.
Fungal infections are a major public health threat, especially HIV patients, immunocompromised hematopoietic stem cell transplant (HSCT) and chemotherapy patients or patients with primary immunodeficiency
.
Recent studies have also found that many fungal species multiply in the intestines of COVID-19 patients
.
Many types of fungi can cause invasive fungal infections (IFI), and about 1.
5 million people die from IFI every year
.
Candida albicans is one of the most common opportunistic fungal pathogens in humans
.
Although several antifungal drugs are effective, the mortality rate of Candida infection exceeds 40%
.
There are currently limited antifungal drugs used for IFI treatment, which may cause adverse side effects
.
In addition, the rapid emergence of drug resistance is a growing problem
.
Therefore, a better understanding of how the host immune system fights fungal infections is essential for the development of new treatment strategies against candidiasis
.
During fungal infections, CLR and Toll-like receptors (TLR) play an important role in the host's defense against fungal pathogens by recognizing various fungal surface components
.
CLR is mainly expressed on neutrophils, macrophages and dendritic cells, such as Dectin-1, Dectin-2, Dectin-3 and Mincle, which recognize fungal β-glucan, α-mannan and Glycolipid
.
After recognizing the corresponding ligand, the CLR initiates phosphorylation of the Tyr-XX-leu motif (called "ITAM") in the cytoplasmic tail of Dectin-1, and recruits FcRγ to Dectin-2 or Mincle, which serves as a docking station for SYK Site
.
These events promote SYK translocation and activation, which then activate PLCγ and PKCδ
.
CARD9, BCL10, and MALT1 then form a CARD9-BCL10-MALT1 (CBM) complex to activate mitogen-activated protein (MAP) kinase, as well as NF-κB and NFAT transcription factors, leading to the production of pro-inflammatory cytokines and chemokines
.
In addition, these cytokines and chemokines promote neutrophil infiltration, macrophage maturation and T cell differentiation
.
It has been proved that the Th1 and Th17 subpopulations of T helper cells participate in the host's defense against fungal infections by producing IFN-γ, IL-17A and IL-17F, and further activate and recruit macrophages and neutrophils
.
SYK is a non-receptor tyrosine kinase that contains two Src homology 2 (SH2) domains and a carboxy-terminal kinase domain
.
In addition, there are two domains (called interdomain A and B) located between the two SH2 domains and between the kinase domain and the second SH2 domain
.
Due to the binding of inter-domain A and inter-domain B to the kinase domain, SYK is present in the autoinhibitory structure, which prevents access to the substrate of the catalytic domain in resting cells
.
As an important linker and kinase of the CLR signaling complex close to the plasma membrane, SYK activity must be fine-tuned during fungal infection
.
However, in addition to CBL-B, whether other E3 ubiquitin ligases modify the activation of SYK is completely unknown
.
The member of the Tripartite motif (TRIM) family of proteins is the well-known E3 ubiquitin ligase, which contains a conserved ring finger domain, one or two B-boxes, and a coiled-coil domain
.
The TRIM family is involved in various biological processes, including the fight against HIV and tumor progression by regulating K48 or K63-linked polyubiquitination to the target
.
Several members, including TRIM10, TRIM15, TRIM26, TRIM27, TRIM31, TRIM38, TRIM39, and TRIM40, have been shown to participate in the innate immune response, possibly due to the coding genes located at the locus that encode major histocompatibility complex (MHC) class I proteins
.
So far, few reports on the role of the TRIM family in the process of fungal infections have been reported
.
In this study, several important members of the TRIM family were screened to study the possible role of this family in regulating SYK activity during fungal infections
.
The study found that TRIM31 is an essential positive regulator for SYK
.
In particular, TRIM31 catalyzes K27-linked polyubiquitination at Lys375 and Lys517 of SYK, which subsequently promotes SYK translocation and binding to CLR, and reduces the binding of SYK to phosphatase SHP-1
.
Therefore, this up-regulates SYK kinase phosphorylation and activity
.
TRIM31 protects the host from the lethal systemic infection of Candida albicans in the mouse model by increasing the production of pro-inflammatory cytokines and chemokines, which helps to eliminate pathogens more effectively
.
Overall, this study first reported that SYK was modified by TRIM31 by K27-linked polyubiquitination after fungal infections, and also revealed that it is actively regulating the activation of SYK-related signal cascades and the resulting antifungal immunity.
The importance of
.
Reference message: https://
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNature spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase that plays a vital role in both innate and adaptive immunity
.
However, the key molecular mechanisms that regulate SYK activity are poorly understood
.
On August 6, 2021, the Gao Chengjiang team of Shandong University published an online research paper titled "TRIM31 facilitates K27-linked polyubiquitination of SYK to regulate antifungal immunity" in Signal Transduction and Targeted Therapy (IF=18.
19).
This research combines E3 ligase TRIM31 was identified as a key regulator of SYK activation
.
The study found that TRIM31 interacts with SYK and catalyzes the polyubiquitination of Lys375 of SYK and K27 of Lys517
.
This K27-linked polyubiquitination of SYK promotes its plasma membrane translocation and binding to the C-type lectin receptor (CLR), and prevents the interaction with the phosphatase SHP-1
.
Therefore, the lack of Trim31 in bone marrow-derived dendritic cells (BMDC) and macrophages (BMDM) inhibits SYK-mediated signal transduction and inhibits pro-inflammatory cytokines and chemokines against the fungal pathogen Candida albicans infection Secretion
.
Trim31-/- mice are also more sensitive to systemic Candida albicans infection than Trim31+/+ mice, and show reduced Th1 and Th17 responses
.
Overall, this study revealed the key role of TRIM31-mediated K27-linked polyubiquitination on SYK activation and emphasized the importance of TRIM31 in anti-Candida albicans immunity
.
Fungal infections are a major public health threat, especially HIV patients, immunocompromised hematopoietic stem cell transplant (HSCT) and chemotherapy patients or patients with primary immunodeficiency
.
Recent studies have also found that many fungal species multiply in the intestines of COVID-19 patients
.
Many types of fungi can cause invasive fungal infections (IFI), and about 1.
5 million people die from IFI every year
.
Candida albicans is one of the most common opportunistic fungal pathogens in humans
.
Although several antifungal drugs are effective, the mortality rate of Candida infection exceeds 40%
.
There are currently limited antifungal drugs used for IFI treatment, which may cause adverse side effects
.
In addition, the rapid emergence of drug resistance is a growing problem
.
Therefore, a better understanding of how the host immune system fights fungal infections is essential for the development of new treatment strategies against candidiasis
.
During fungal infections, CLR and Toll-like receptors (TLR) play an important role in the host's defense against fungal pathogens by recognizing various fungal surface components
.
CLR is mainly expressed on neutrophils, macrophages and dendritic cells, such as Dectin-1, Dectin-2, Dectin-3 and Mincle, which recognize fungal β-glucan, α-mannan and Glycolipid
.
After recognizing the corresponding ligand, the CLR initiates phosphorylation of the Tyr-XX-leu motif (called "ITAM") in the cytoplasmic tail of Dectin-1, and recruits FcRγ to Dectin-2 or Mincle, which serves as a docking station for SYK Site
.
These events promote SYK translocation and activation, which then activate PLCγ and PKCδ
.
CARD9, BCL10, and MALT1 then form a CARD9-BCL10-MALT1 (CBM) complex to activate mitogen-activated protein (MAP) kinase, as well as NF-κB and NFAT transcription factors, leading to the production of pro-inflammatory cytokines and chemokines
.
In addition, these cytokines and chemokines promote neutrophil infiltration, macrophage maturation and T cell differentiation
.
It has been proved that the Th1 and Th17 subpopulations of T helper cells participate in the host's defense against fungal infections by producing IFN-γ, IL-17A and IL-17F, and further activate and recruit macrophages and neutrophils
.
SYK is a non-receptor tyrosine kinase that contains two Src homology 2 (SH2) domains and a carboxy-terminal kinase domain
.
In addition, there are two domains (called interdomain A and B) located between the two SH2 domains and between the kinase domain and the second SH2 domain
.
Due to the binding of inter-domain A and inter-domain B to the kinase domain, SYK is present in the autoinhibitory structure, which prevents access to the substrate of the catalytic domain in resting cells
.
As an important linker and kinase of the CLR signaling complex close to the plasma membrane, SYK activity must be fine-tuned during fungal infection
.
However, in addition to CBL-B, whether other E3 ubiquitin ligases modify the activation of SYK is completely unknown
.
The member of the Tripartite motif (TRIM) family of proteins is the well-known E3 ubiquitin ligase, which contains a conserved ring finger domain, one or two B-boxes, and a coiled-coil domain
.
The TRIM family is involved in various biological processes, including the fight against HIV and tumor progression by regulating K48 or K63-linked polyubiquitination to the target
.
Several members, including TRIM10, TRIM15, TRIM26, TRIM27, TRIM31, TRIM38, TRIM39, and TRIM40, have been shown to participate in the innate immune response, possibly due to the coding genes located at the locus that encode major histocompatibility complex (MHC) class I proteins
.
So far, few reports on the role of the TRIM family in the process of fungal infections have been reported
.
In this study, several important members of the TRIM family were screened to study the possible role of this family in regulating SYK activity during fungal infections
.
The study found that TRIM31 is an essential positive regulator for SYK
.
In particular, TRIM31 catalyzes K27-linked polyubiquitination at Lys375 and Lys517 of SYK, which subsequently promotes SYK translocation and binding to CLR, and reduces the binding of SYK to phosphatase SHP-1
.
Therefore, this up-regulates SYK kinase phosphorylation and activity
.
TRIM31 protects the host from the lethal systemic infection of Candida albicans in the mouse model by increasing the production of pro-inflammatory cytokines and chemokines, which helps to eliminate pathogens more effectively
.
Overall, this study first reported that SYK was modified by TRIM31 by K27-linked polyubiquitination after fungal infections, and also revealed that it is actively regulating the activation of SYK-related signal cascades and the resulting antifungal immunity.
The importance of
.
Reference message: https://
