LST1: A Gene with Extensive Alternative Splicing and Immunomodulatory Function

Abstract

The gene of the leukocyte-specific transcript (LST1) is encoded within the TNF region of the human MHC. The LST1 gene is constitutively expressed in leukocytes and dendritic cells, and it is characterized by extensive alternative splicing. We identified 7 different LST1 splice variants in PBMC; thus, 14 LST1 splice variants (LST1/A-LST1/N) have been detected in various cell types. These isoforms code for transmembrane as well as soluble LST1 proteins characterized by two alternative open reading frames at their 3′ end. We demonstrate the presence of the transmembrane variant LST1/C on the cell surface of the monocytic cell lines U937 and THP1. Recombinant expression of LST1/C permitted its profound inhibitory effect on lymphocyte proliferation to be observed. In contrast, the alternative transmembrane variant LST1/A, the extracellular domain of which shows no amino acid sequence homology to LST1/C exerted a weaker but similar inhibitory effect on PBMC. These data demonstrate the protein expression of LST1 on the cell surface of mononuclear cells, and they show an inhibitory effect on lymphocyte proliferation of two LST1 proteins although they have only a very short amino acid homology.

LST1/A Is a Myeloid Leukocyte-specific Transmembrane Adaptor Protein Recruiting Protein Tyrosine Phosphatases SHP-1 and SHP-2 to the Plasma Membrane

“…It revealed that LST1/A is substantially enriched in the spleen, peripheral blood monocytes, and granulocytes, as well as the cell lines of myeloid origin, indicating that LST1/A is expressed predominantly in the leukocytes of myeloid lineage. Although this conclusion is only in partial agreement with previously published studies (1,3,(5)(6)(7)(8), we consider our results reliable for several reasons. 1) We analyzed LST1/A expression profile in primary tissues and blood subpopulations, as well as in cell lines both at the protein and the mRNA levels and obtained a set of mutually supporting data.…”

“…The human LST1 primary transcript has been reported to undergo extensive alternative splicing resulting in a large number of splice variants. However, only limited alternative splicing has been reported for the mouse homologue (5,6). Translation of LST1 splice isoforms would lead to the synthesis of various soluble and membrane-bound protein products.…”

T Cell-Specific Expression of the Human TNF-α Gene Involves a Functional and Highly Conserved Chromatin Signature in Intron 3

“…4. dendritic cells and encodes a small protein that modulates the immune response and cellular morphogenesis (22,23). Only THP-1 and Jurkat cells, which both express the LST1 gene product in a constitutive fashion, display a constitutive DH site in the same segment of the 5Ј-flanking region (see DH sites 3 and 9 in Fig.…”

Haplotype-specific gene expression profiles in a telomeric major histocompatibility complex gene cluster and susceptibility to autoimmune diseases

“…17 Fourteen splice variants in total have been detected including some with and some without transmembrane domains implying that there may be secreted and cell surface forms of the protein. The mRNA encoding seven of these variants has been detected in dendritic cells and leucocytes.…”