Успехи молекулярной онкологии

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Endocytosis of the IFNAR1 chain of Type 1 interferon receptor is regulated by diverse E2 ubiquitin conjugation enzymes

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Ubiquitination of signaling receptors triggers their endocytosis to restrict the extent of cell signaling. Type 1 interferon (IFN1) eliminates its receptor from cell surface via stimulating the ubiquitination of its IFNAR1 chain. While it was suggested that this ubiquitination aids IFNAR1
internalization via relieving a steric hindrance of a linear motif within IFNAR1 from the endocytic machinery, the mechanisms involved remain poorly understood. Here we describe a specific role for two disparate ubiquitin acceptor sites within this receptor. These sites, Lys501 and Lys525 / 526, exhibit a preference for polyubiquitination via either Lys63- or Lys48‑linked chains (K63‑Ub and K48‑Ub, respectively). Whereas the SCFβTrcp E3 ubiquitin ligase controls either type of ubiquitination-dependent IFNAR1 endocytosis, the specificity of these processes is determined by two different E2 ubiquitin conjugating enzymes, Ubc13 and Cdc34. These enzymes can be directly used by SCFβTrcp E3 ubiquitin ligase to generate either K63‑Ub or K48‑Ub in vitro. Ubc13 is involved in IFNAR1 endocytosis driven by the K63‑Ub modification of Lys501, whereas the K48‑Ub-specific Cdc34 affects receptor endocytosis via ubiquitin conjugation that occurs on Lys525 / 526. Both types of linkages combine to maximize IFNAR1 endocytosis otherwise suppressed by unfavorable conformation dependent on the presence of a conserved Pro470 within the intracellular domain of IFNAR1. We propose a model where alternate utilization of both E2s to assemble diverse polyubiquitin linkages cooperates to achieve IFNAR1 intracellular domain conformations and spatial arrangements that favor a maximal rate of receptor endocytosis.

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Об авторах

Christopher J. Carbone
Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, 380 S. University Avenue, Hill 316, Philadelphia, PA 19104, USA

Hui Zheng
Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, 380 S. University Avenue, Hill 316, Philadelphia, PA 19104, USA

Serge Y. Fuchs
Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, 380 S. University Avenue, Hill 316, Philadelphia, PA 19104, USA

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Для цитирования:

J. Carbone C., Zheng H., Y. Fuchs S. Endocytosis of the IFNAR1 chain of Type 1 interferon receptor is regulated by diverse E2 ubiquitin conjugation enzymes. Успехи молекулярной онкологии. 2014;1(2):50-60.

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