Key Element Involved in Innate Immune Signaling Identified

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Researchers from the lab of Giulio Superti-Furga, PhD, at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, in collaboration with Boehringer Ingelheim, say they have identified a new key element of the multi-component machinery that is responsible for sorting out the nature and severity of a pathogen challenge to the immune system.

The new protein, named TASL, is indispensable for the signaling of so-called Toll-like receptors (TLR) in the endosomes leading to activation of the gene-activator IRF5 in certain immune cells, according to the scientists. Sensitive “tuning” of the machinery is highly important as too much output causes inflammation also in the absence of the pathogen, as in auto-immune diseases. This particular version of the machinery seems particularly associated with disorders such as systemic lupus erythematosus (SLE). The discovery, which is described in an article “TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7–9” in Nature,  highlights a potential new target for the development of drugs to treat certain autoimmune diseases and possibly also overreaction to viral and other infections.

“Toll-like receptors (TLRs) have a crucial role in the recognition of pathogens and initiation of immune responses. Here we show that a previously uncharacterized protein encoded by CXorf21—a gene that is associated with systemic lupus erythematosus—interacts with the endolysosomal transporter SLC15A4, an essential but poorly understood component of the endolysosomal TLR machinery also linked to autoimmune disease. Loss of this type-I-interferon-inducible protein, which we refer to as ‘TLR adaptor interacting with SLC15A4 on the lysosome’ (TASL), abrogated responses to endolysosomal TLR agonists in both primary and transformed human immune cells. Deletion of SLC15A4 or TASL specifically impaired the activation of the IRF pathway without affecting NF-κB and MAPK signaling, which indicates that ligand recognition and TLR engagement in the endolysosome occurred normally,” write the investigators.

“Extensive mutagenesis of TASL demonstrated that its localization and function relies on the interaction with SLC15A4. TASL contains a conserved pLxIS motif (in which p denotes a hydrophilic residue and x denotes any residue) that mediates the recruitment and activation of IRF5. This finding shows that TASL is an innate immune adaptor for TLR7, TLR8 and TLR9 signaling, revealing a clear mechanistic analogy with the IRF3 adaptors STING, MAVS and TRIF. The identification of TASL as the component that links endolysosomal TLRs to the IRF5 transcription factor via SLC15A4 provides a mechanistic explanation for the involvement of these proteins in systemic lupus erythematosus.”

Previous studies revealed that SLC15A4, a member of the body’s biggest family of transporter proteins, was known as an essential component required for the correct function of these TLRs. Based on their strong research interests in pathogen-sensing by the innate immune system and the characterization of solute carriers, researchers in the Superti-Furga group set out to investigate how SLC15A4 influences the ability of TLRs to sense pathogens, and, consequently, gain a better understanding on its implication in autoimmune conditions, and in particular SLE.

Manuele Rebsamen, Leonhard Heinz, and Giulio Superti-Furga [Laura Alvarez / CeMM]
In their study, first author Leonhard Heinz, PhD, and the team, including Boehringer Ingelheim researchers in Ridgefield, CT, undertook a precise investigative work, not taking for granted previous findings on SLC15A4 and the connection to this group of specially located TLRs. They painstakingly determined by biochemistry and mass spectrometry the molecular interactions that involved SLC15A4. This led to the identification of an uncharacterized protein CXorf21, belonging to the functionally orphan genes that are merely numbered and assigned to the chromosome of origin. The gene, like SLC15A4, had been previously loosely associated with SLE.

The team demonstrated that the interaction between TASL and SLC15A4 was crucial for the localization and function of the TASL protein and could pinpoint the precise involved portions of both proteins. A eureka moment for the understanding of the protein came with the observation that TASL harbors a specific motif essential for the recruitment and activation of IRF5.

“After STING, MAVS and TRIF, the new protein TASL is the fourth key innate immunity adaptor functioning as a platform for the encounter of a kinase and a gene activator of the IRF family,” says Manuele Rebsamen, PhD, CeMM senior postdoctoral fellow and project leader of the study.

These findings raise the possibility that interfering pharmacologically with the SLC15A4/TASL complex could allow the regulation of TLR responses and, consequently, modulate inflammatory responses in the body.

“It was clear to us that SLC15A4 plays a key role in endosomal TLR function and is involved in disease, but the underlying mechanism was not understood. These are exactly the exciting scientific questions that we love to address at our institute, “notes Superti-Furga. “We are happy that the vision we share with Boehringer Ingelheim regarding Solute Carriers being a group of disease-relevant proteins worthy of investigation was rewarded in this successful and exciting partnership.”

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