Galectin-1 Binds Different CD43 Glycoforms to Cluster CD43 and Regulate T Cell Death

Abstract

Galectin-1 kills immature thymocytes and activated peripheral T cells by binding to glycans on T cell glycoproteins including CD7, CD45, and CD43. Although roles for CD7 and CD45 in regulating galectin-1-induced death have been described, the requirement for CD43 remains unknown. We describe a novel role for CD43 in galectin-1-induced death, and the effects of O-glycan modification on galectin-1 binding to CD43. Loss of CD43 expression reduced galectin-1 death of murine thymocytes and human T lymphoblastoid cells, indicating that CD43 is required for maximal T cell susceptibility to galectin-1. CD43, which is heavily O-glycosylated, contributes a significant fraction of galectin-1 binding sites on T cells, as T cells lacking CD43 bound ∼50% less galectin-1 than T cells expressing CD43. Although core 2 modification of O-glycans on other glycoprotein receptors is critical for galectin-1-induced cross-linking and T cell death, galectin-1 bound to CD43 fusion proteins modified with either unbranched core 1 or branched core 2 O-glycans and expression of core 2 O-glycans did not enhance galectin-1 binding to CD43 on T cells. Moreover, galectin-1 binding clustered CD43 modified with either core 1 or core 2 O-glycans on the T cell surface. Thus, CD43 bearing either core 1 or core 2 O-glycans can positively regulate T cell susceptibility to galectin-1, identifying a novel function for CD43 in controlling cell death. In addition, these studies demonstrate that different T cell glycoproteins on the same cell have distinct requirements for glycan modifications that allow recognition and cross-linking by galectin-1.

CD43 in the nucleus and cytoplasm of lung cancer is a potential therapeutic target

“…Changes in the glycosylation pattern of its extracellular domain allow CD43 to function as a proadhesive counter receptor for galectin-1, ICAM-1, E-selectin, sialoadhesin and MHC Class I molecules. 16,23,[25][26][27][28]37,39,40 While CD43 is normally restricted in its expression to leukocytes and platelets, aberrant expression has been consistently described in colon and salivary gland cancers. [41][42][43][44] In addition, limited analysis suggested that NSCLC but not SCLC might also be characterized by CD43 expression.…”

Functions of cell surface galectin-glycoprotein lattices

“…This multivalency also allows the formation of lectin-carbohydrate lattices. Both in solution and on the cell surface, multivalent galectins selectively cross-link a single species of glycoprotein to form homogeneous lectin-carbohydrate lattices [5,17,19].…”

“…Galectin-1, -2, -3 and -9 bind distinct cell surface glycoprotein receptors and trigger distinct intracellular signaling pathways to promote T-cell death [17,19,[35][36][37]. Remarkably, a number of factors determine the responsiveness of cells to galectin-mediated signals which include the repertoire of glycosylated molecules expressed on the cell surface and the activities of specific glycosyltransferases, which are responsible for creating or masking galectin ligands [5,6,18].…”

Conformational consequences of protein glycosylation: Preparation of O‐mannosyl serine and threonine building blocks, and their incorporation into glycopeptide sequences derived from α‐dystroglycan

“…2 These glycoproteins can display a variety of carbohydrate epitopes, making them versatile participants in cellular recognition. The variation of the pendant carbohydrate epitopes reflects cell development and condition, [3][4][5] contributing to the modulation of cell-cell interactions, as well as mediating cellular responses to other proteins in the extracellular milieu through effects on localization of the cytoplasmic portions of these cell surface molecules. 3 Such glycoproteins also present potential therapeutic targets particularly in tumor cells, 6 being set apart by aberrant mucin protein glycosylation.…”