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In a seminal paper published in Nature, Heinz et al provide important new information on the gene product of CXorf21, an X-linked gene associated with systemic lupus erythematosus (SLE).1 Using an impressive array of molecular techniques, these investigators demonstrated that the protein encoded by a gene originally known as CXorf21 interacts with SLC15A4, an amino acid transporter in the endolysosomal compartment; the gene for SLC15A4 has also been genetically associated with SLE. While the role of CXorf21 in SLE had been investigated for many years, the function of its protein product was a mystery until Heinz et al identified it as an adaptor in TLR signalling. The name for this protein is now ‘TLR adaptor interacting with endolysosomal SLC15A4’ or TASL; the gene is designated as TASL (CXorf21).
As the studies in THP1 and other human cells in the Nature paper illustrate, TASL is important for the recruitment and activation of the transcription factor IRF5 in downstream signalling by TLR 7, 8 and 9; as such, TASL has analogy with adaptor proteins like STING, MAVS and TRIF. These findings are relevant to the pathogenesis of SLE since, in this disease, DNA and RNA in the form of immune complexes can enter cells of the innate immune system to induce responses by TLR 7, 8 and 9 in the endosomes; the production of interferon and other proinflammatory cytokines is an outcome of this pathway. Interestingly, in its regulation of gene expression, TASL affects the IRF pathway but does not affect NF-κB or MAPK signalling.1 This pattern points to a unique role of TASL in the activation of innate immunity by the endosomal TLRs (figure 1).
Handling editor Josef S Smolen
Correction notice This article has been corrected since it published Online First. Figure 1 has been corrected.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Commissioned; internally peer reviewed.