Diversification of TOLLIP isoforms in mouse and man.
The Toll-interacting protein TOLLIP is an ubiquitin-binding protein that interacts with several components of the Toll-like receptor signaling cascade. The canonical protein consists of three annotated domains: an N-terminal TBD-loop-coil domain that mediates protein-protein interactions, a C2 domain that targets TOLLIP to the endosome, and a CUE domain at the C-terminus that binds monoubiquitin. TOLLIP has been described primarily in trafficking of the interleukin-1 receptor (IL1R) and turnover of the interleukin-1 receptor-associated kinase (IRAK), so it is an essential regulator of inflammatory signaling. Here we describe the expression of numerous alternate transcripts from mouse and human TOLLIP, which are predicted to generate at least five variant proteins between the two species. Most of the variant proteins are predicted to have altered N-terminal domains, altered TBD-loop-coil domains, or a truncated C2 domain. A mouse-specific variant arises from an alternate termination exon, and the resulting protein lacks the CUE domain. Two transcripts arising from alternate initiating exons are highly conserved between mouse and human but exhibit different patterns of expression. The consequent protein isoforms retain (TOLLIP.A) or lack (TOLLIP.D) the protein-binding TBD, so are predicted to traffic monoubiquitinated proteins to alternate protein complexes within the endosomal compartment. In summary, the widespread and inducible expression of Tollip isoforms predicts diversification of its function in rodent and human immune systems. Alternate splicing of critical signaling molecules such as Tollip may provide one mechanism behind the broad repertoire of responses generated by cells of the innate immune system in response to infection.
Lo
Yu-Lan S
YL
The National Centre for Adult Stem Cell Research, The Eskitis Institute for Cell and Molecular Therapies, Griffith University, QLD, Australia.
Beckhouse
Anthony G
AG
Boulus
Sharon L
SL
Wells
Christine A
CA
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009000:Monocytes / Q000737:chemistry / Q000378:metabolism; D009928:Organ Specificity; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012326:RNA Splicing
D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; C410602:TOLLIP protein, human; C485837:Tollip protein, mouse