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TLR ADAPTOR INTERACTING WITH ENDOLYSOSOMAL SLC15A4; TASL

TLR ADAPTOR INTERACTING WITH ENDOLYSOSOMAL SLC15A4; TASL

Alternative titles; symbolsCHROMOSOME X OPEN READING FRAME 21; CXORF21HGNC Approved Gene Symbol: TASLCytogenetic location: Xp21.2 Genomic coordinates (GRCh38...

Alternative titles; symbols

  • CHROMOSOME X OPEN READING FRAME 21; CXORF21

HGNC Approved Gene Symbol: TASL

Cytogenetic location: Xp21.2 Genomic coordinates (GRCh38): X:30,558,808-30,577,765 (from NCBI)

▼ Description
CXORF21 is an X chromosome-encoded gene that escapes X-inactivation and displays female-biased expression (Harris et al., 2019). CXORF21 is involved in initiation of immune responses by linking endolysosomal Toll-like receptors (e.g., TLR7; 300365) to the IRF5 (607218) transcription factor via SLC15A4 (615806) (Heinz et al., 2020).

▼ Cloning and Expression
Harris et al. (2019) found that CXORF21 mRNA and protein were expressed in human primarily monocytes, dendritic cells, B lymphocytes, and lymphoblastoid cell lines (LCLs), but not in primary T cells or natural killer (NK) cells, with higher levels in female than male cells.

Heinz et al. (2020) stated that CXORF21, which they termed TASL, is a 301-amino acid protein that is conserved in vertebrates.

▼ Mapping
Gross (2020) mapped the CXORF21 gene to chromosome Xp21.2 based on an alignment of the CXORF21 sequence (GenBank BC020611) with the genomic sequence (GRCh38).

▼ Gene Function
Harris et al. (2019) stated that CXORF21 and SLC15A4 are binding partners at the lysosomal membrane. They found that female human immune cells that expressed CXORF21 had lower lysosomal pH compared with the same cells from males. In contrast, cells that expressed minimal levels of CXORF21 showed no gender-based difference in lysosomal pH.

Using quantitative RT-PCR analysis, Harris et al. (2019) found that CXORF21 expression was higher in LCLs from both male and female patients with systemic lupus erythematosus (SLE; 152700) compared with controls. Knockdown of CXORF21 in primary female monocytes increased lysosomal pH and disrupted SLC15A4 function and regulation of TLR7 expression. CXORF21 knockdown also abrogated TLR7-driven increase of IFNA1 (147660) expression and reduced secretion of both TNF-alpha (191160) and IL6 (147620) in healthy female monocytes.

Using proteomic analysis, Heinz et al. (2020) found that type I interferon induced TASL expression and that TASL bound specifically to SLC15A4. TASL localization and function relied on interaction with SLC15A4, and SLC15A4 binding required the N-terminal region of TASL. Expression and knockout experiments in THP1 human monocytes showed that the TASL-SLC15A4 complex was required for IRF5-dependent endolysosomal TLR-induced inflammatory responses. Sequence analysis revealed a highly conserved pLxIS motif (in which p denotes a hydrophilic residue, and x denotes any residue) in the C-terminal region of TASL that allowed TASL to act as an innate immune adaptor for recruitment and activation of IRF5 by TLR7, TLR8 (300366), and TLR9 (605474).

Tags: Xp21.2