An LI and ML motif in the cytoplasmic tail of the MHC-associated invariant chain mediate rapid internalization

Bremnes, Bjørn; Madsen, Thomas Daugbjerg; Gedde-Dahl, Merete; Bakke, Oddmund

doi:10.1242/jcs.107.7.2021

Cited by 119 publications

(1 citation statement)

References 49 publications

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“…1F-G). This low detection of CD74 by surface staining is consistent with the elevated recycling property of this molecule (11,12). In sharp contrast, 80.8 ± 4.3 % (mean ± SD) of Tconvs and 99.6 ± 0.3 % (mean ± SD) of Tregs expressed CD74 intracellularly.…”

Section: Tumor-associated Tregs Upregulate Surface Cd74supporting

confidence: 74%

CD74 supports Treg accumulation and function in tumors

Bonnin

Denizeau

Sáez

et al. 2023

Preprint

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Regulatory T cells (Tregs) are plastic cells playing a pivotal role in the maintenance of immune homeostasis. Tregs actively adapt to the microenvironment where they reside; as a consequence, their molecular and functional profiles differ among tissues and pathologies. In tumors, the features acquired by Tregs remains poorly characterized. Here, we observed that human tumor-infiltrating Tregs selectively overexpress CD74, the MHC class II invariant chain. CD74 has been previously described as a regulator of antigen-presenting cell biology, however its function in Tregs remains unknown. CD74 genetic deletion in human primary Tregs revealed that CD74KO Tregs exhibit major defects in the organization of their actin cytoskeleton and intracellular organelles. Additionally, intra-tumoral CD74KO Tregs show a decreased activation, a drop in Foxp3 expression, a low accumulation in the tumor, and consistently, they accelerate the tumor rejection. These observations are unique to tumor conditions as, at steady state, CD74KO-Treg phenotype, survival, and suppressive capacity are unaffected in vitro and in vivo. CD74 therefore emerges as a specific regulator of tumor-infiltrating Tregs and as a novel target to interfere with Treg anti-tumor activity.

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Section: Tumor-associated Tregs Upregulate Surface Cd74supporting

confidence: 74%

CD74 supports Treg accumulation and function in tumors

Bonnin

Denizeau

Sáez

et al. 2023

Preprint

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The transmembrane segment of invariant chain mediates binding to MHC class II molecules in a CLIP-independent manner

2001

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Invariant chain (Ii) association with MHC class II molecules is strongly dependent upon interaction of CLIP (Ii exon 3, residues 81 – 104) with the peptide binding groove of the class II dimer. This dominant interaction does not adequately explain, however, the efficient association of Ii with class II molecules of diverse allelic and isotypic origin, which have markedly different affinities for synthetic peptides corresponding to CLIP. In agreement with other recent observations, we demonstrate here that class II molecules with occupied binding sites unable to engage CLIP maintain association with Ii in mild detergent. The association is direct and not mediated through unoccupied class II chains bound to properly assembled and loaded class II dimers, nor is it mediated through chaperones. The site of this CLIP‐independent binding has been mapped using truncation mutants and an Ii‐human transferrin receptor chimeric protein to the transmembrane segment of Ii. The existence of multiple low‐affinity sites of interaction between MHC class II and Ii helps explain how effective occupancy of all newly synthesized class II molecules can occur despite substantial variations in the strength of CLIP‐dependent association that arise from class II binding domain polymorphism. These data establishing a site of Ii‐MHC class II association N‐terminal to CLIP also provide new insight into the possible functional relationship between the sequential endocytic proteolysis of Ii from its C terminus and a series of contact sites with MHC class II molecules spread from the transmembrane region through to the tip of the lumenal segment of Ii.

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Design of transgenes for efficient expression of active chimeric proteins on mammalian cells

Liao

Chou

et al. 2001

Biotech & Bioengineering

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Heterologous proteins expressed on the surface of cells may be useful for eliciting therapeutic responses and engineering new extracellular properties. We examined factors that control the membrane targeting of ␣-fetoprotein (AFP) and a single-chain antibody (scFv). Chimeric proteins were targeted to the plasma membrane by employing the transmembrane domain (TM) and cytosolic tail of murine CD8O (B7-1), the TM of the human platelet-derived growth factor receptor (PDGFR), the glycosylphosphatidylinositol anchor encoded by the C-terminal extension of decay-accelerating factor (DAF), and the TM of the H1 subunit of the human asialoglycoprotein receptor (ASGPR). AFP chimeric proteins containing the B7, DAF, ASGPR, or PDGFR targeting domains displayed half-lives of 12.2, 3.8, 2.4, and 1.6 h, respectively. The newly synthesized B7 chimera was rapidly transported and remained on the cell surface. Glycosylphosphatidylinositol-anchored chimeras reached the surface more slowly and significant amounts were released into the culture medium. PDGFR TM chimeras were rapidly degraded, whereas ASGPR chimeras were retained in the endoplasmic reticulum (ER). The surface expression of both AFP and scFv chimeric proteins followed the order (highest to lowest) of B7 > DAF >> PDGFR. Introduction of a dimerization domain (hinge-CH 2 -CH 3 region of human IgG1) between scFv and TM dramatically reduced cleavage of the chimeric protein, increased surface expression, and produced biologically active scFv. Our results indicate that transgenes designed for the expression of active scFv on cells should incorporate a TM that does not undergo endocytosis, include an intact cytoplasmic domain, and possess a spacer to reduce cleavage and retain biological activity.

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An LI and ML motif in the cytoplasmic tail of the MHC-associated invariant chain mediate rapid internalization

Cited by 119 publications

References 49 publications

CD74 supports Treg accumulation and function in tumors

CD74 supports Treg accumulation and function in tumors

The transmembrane segment of invariant chain mediates binding to MHC class II molecules in a CLIP-independent manner

Design of transgenes for efficient expression of active chimeric proteins on mammalian cells

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