Hrs Recognizes a Hydrophobic Amino Acid Cluster in Cytokine Receptors during Ubiquitin-independent Endosomal Sorting

Amano, Yuji; Yamashita, Yūki; Kojima, Kentaro; Yoshino, Kazuhisa; Tanaka, Nobuyuki; Sugamura, Kazuo; Takeshita, Toru

doi:10.1074/jbc.m110.191924

Cited by 13 publications

(11 citation statements)

References 52 publications

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“…A mutated form of Hrs, deleted from the UIM, presented a similar increase of tyrosine phosphorylation after stimulation by IFN-α ( Fig. 1E), suggesting that IFNAR1 ubiquitination was not required for Hrs interaction and phosphorylation, as already reported for other cytokine receptors (16). This result is also consistent with our finding that only IFN-α and not IFN-β promotes the interaction of IFNAR1 with Hrs, whereas both IFN-α and IFN-β can induce the ubiquitylation of IFNAR1 subunits (17,18).…”

Section: Ifnar1 Interacts With Hrs At the Early Endosomesupporting

confidence: 76%

STAM Interaction with Hrs Controls JAK/STAT Activation by Interferon-α at the Early Endosome

Zanin

Blouin

et al. 2019

Preprint

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Activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway by type I interferons (IFN) requires clathrin-dependent endocytosis of the IFN-α/β receptor (IFNAR). The molecular machinery that brings about the selective activation of IFN-α/β-induced JAK/STAT signaling on endosomes remains unknown. Here we show that the constitutive association of STAM with IFNAR1 and the TYK2 Janus kinase at the plasma membrane prevents the activation of TYK2 by type I IFNs. IFN-α stimulated endocytosis leads to the interaction of IFNAR1 with Hrs on early endosomes, which then relieves TYK2 inhibition by STAM and thereby allows for TYK2 and IFNAR signaling. In contrast, IFN-β stimulation results in sorting of IFNAR to a distinct endosomal subdomain where the receptor is activated independently from Hrs. Our results identify the molecular machinery that controls the spatiotemporal activation of TYK2 and establish the central role of endosomal sorting in the differential regulation of JAK/STAT signaling by IFN-α and IFN-β.

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Section: Ifnar1 Interacts With Hrs At the Early Endosomesupporting

confidence: 76%

STAM Interaction with Hrs Controls JAK/STAT Activation by Interferon-α at the Early Endosome

Zanin

Blouin

et al. 2019

Preprint

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“…While HGS is better known for its ability to target the ubiquitin-modified cargoes [ 67 , 68 ], it has also been shown to recognize a motif of clustering hydrophobic amino acids in cytokine receptors IL-2Rb and IL-4Ra, in an ubiquitin-independent manner [ 69 , 70 ]. Similarly, our result from the co-IP experiment suggested that the HGS protein could be associated with the assembly domain of HBc in a manner independent of the potential ubiquitination sites in both HGS (UIM domain) and HBc (K7, K96) ( Fig 7 ).…”

Section: Discussionmentioning

confidence: 99%

The Dual Role of an ESCRT-0 Component HGS in HBV Transcription and Naked Capsid Secretion

et al. 2015

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The Endosomal Sorting Complex Required for Transport (ESCRT) is an important cellular machinery for the sorting and trafficking of ubiquitinated cargos. It is also known that ESCRT is required for the egress of a number of viruses. To investigate the relationship between ESCRT and hepatitis B virus (HBV), we conducted an siRNA screening of ESCRT components for their potential effect on HBV replication and virion release. We identified a number of ESCRT factors required for HBV replication, and focused our study here on HGS (HRS, hepatocyte growth factor-regulated tyrosine kinase substrate) in the ESCRT-0 complex. Aberrant levels of HGS suppressed HBV transcription, replication and virion secretion. Hydrodynamic delivery of HGS in a mouse model significantly suppressed viral replication in the liver and virion secretion in the serum. Surprisingly, overexpression of HGS stimulated the release of HBV naked capsids, irrespective of their viral RNA, DNA, or empty contents. Mutant core protein (HBc 1–147) containing no arginine-rich domain (ARD) failed to secrete empty virions with or without HGS. In contrast, empty naked capsids of HBc 1–147 could still be promoted for secretion by HGS. HGS exerted a strong positive effect on the secretion of naked capsids, at the expense of a reduced level of virions. The association between HGS and HBc appears to be ubiquitin-independent. Furthermore, HBc is preferentially co-localized with HGS near the cell periphery, instead of near the punctate endosomes in the cytoplasm. In summary, our work demonstrated the importance of an optimum level of HGS in HBV propagation. In addition to an effect on HBV transcription, HGS can diminish the pool size of intracellular nucleocapsids with ongoing genome maturation, probably in part by promoting the secretion of naked capsids. The secretion routes of HBV virions and naked capsids can be clearly distinguished based on the pleiotropic effect of HGS involved in the ESCRT-0 complex.

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“…33 In these cargos, Hrs recognizes a hydrophobic amino-acid cluster, which is utilized as an ubiquitin-independent sorting signal. 34 Therefore, SARA exhibits all the structural requirements to form an alternative to Hrs ESCRT-0 complex. Indeed, not only do the Hrs-and TSG101independent pathways exist 35,36 but also totally ESCRT-independent mechanisms of multivesicular endosome biogenesis have been predicted to occur.…”

Section: Discussionmentioning

confidence: 99%

SARA and RNF11 interact with each other and ESCRT-0 core proteins and regulate degradative EGFR trafficking

et al. 2012

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Smad anchor for receptor activation (SARA) is highly enriched on endocytic membranes via binding to phosphatidylinositol 3-phosphates through its FYVE (Fab1p-YOTB-Vps27p-EEA1) domain. SARA was originally identified as a protein that recruits non-phosphorylated SMAD2/3 to the activated TGFβ receptors for phosphorylation, but later reports suggested a regulatory role in endocytic trafficking. Here we demonstrate that the ubiquitin ligase RNF11 is a SARA-interacting protein residing on early and late endosomes, as well as the fast recycling compartment. RNF11 and SARA interact with the ESCRT-0 subunits STAM2 and Eps15b, but only RNF11 associates with the core subunit Hrs. Both gain- and loss-of-function perturbation of RNF11 and SARA levels result in delayed degradation of epidermal growth factor (EGF)-activated EGF receptor (EGFR), while loss-of-function sustained/enhanced EGF-induced ERK1/2 phosphorylation. These findings suggest that RNF11 and SARA are functional components of the ESCRT-0 complexes. Moreover, SARA interacts with clathrin, the ESCRT-I subunit Tsg101 and ubiquitinated cargo exhibiting all the properties of Hrs concerning ESCRT-0 function, indicating that it could substitute Hrs in some ESCRT-0 complexes. These results suggest that RNF11 and SARA participate structurally and functionally in the ESCRT-dependent lysosomal degradation of receptors. As a consequence, the negative influence that perturbation of RNF11 and SARA levels exerts on the lysosomal degradation of EGFRs could underscore the reported overexpression of RNF11 in several cancers. In these cancers, deficient termination of the oncogenic signaling of mutated receptors, such as the EGFRs, through suboptimal lysosomal degradation could contribute to the process of malignant transformation.

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Hrs Recognizes a Hydrophobic Amino Acid Cluster in Cytokine Receptors during Ubiquitin-independent Endosomal Sorting

Cited by 13 publications

References 52 publications

STAM Interaction with Hrs Controls JAK/STAT Activation by Interferon-α at the Early Endosome

STAM Interaction with Hrs Controls JAK/STAT Activation by Interferon-α at the Early Endosome

The Dual Role of an ESCRT-0 Component HGS in HBV Transcription and Naked Capsid Secretion

SARA and RNF11 interact with each other and ESCRT-0 core proteins and regulate degradative EGFR trafficking

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