Hypoxia inducible factors (HIF1, 2 and 3), consisting of a and b subunits, play an essential role in various responses to hypoxia. Nuclear entry of a subunits is a necessary step for the formation of DNA-binding complex with b subunit, which is constitutively localized in the nucleus. We show here that the nuclear accumulation of HIF2a induced by hypoxia is mediated through a novel variant of bipartite-type nuclear localization signal (NLS) in the C-terminus of the protein, which has an unusual length of spacer sequence between two adjacent basic domains. We further show that when the ubiquitin-proteasome system was de®cient or inhibited, HIF2a accumulated in the nucleus even under normoxia, also mediated through the bipartite NLS. These ®ndings indicate that the protein stability is critical for the nuclear localization of HIF2a and hypoxia is not a necessary factor for the process. Importantly, the NLS of HIF2a is also conserved in the other HIF family members, HIF1a and HIF3a. Mutational analyses proved that the NLS mediating the nuclear localization of HIF1a is indeed bipartite-, but not monopartite-type as thought before. Our results suggest that the newly identi®ed NLS is crucial for the functional regulation of HIF family.
Background Transthyretin amyloid cardiomyopathy results from the accumulation of wild-type (ATTRwt) or variant (ATTRv) transthyretin amyloid fibrils in the myocardium. THAOS (Transthyretin Amyloidosis Outcomes Survey) is a global, longitudinal, observational survey of patients with ATTRv and ATTRwt amyloidosis and asymptomatic patients with transthyretin mutations. Objectives This study explored temporal trends in ATTRwt amyloidosis diagnoses using data from THAOS. Methods Using THAOS data from December 2007 to January 2020, the following comparisons were made according to year: ATTRwt amyloidosis diagnoses in the United States versus rest of the world, ATTRwt versus ATTRv amyloidosis with cardiac-associated mutations diagnoses, and ATTRwt amyloidosis diagnoses by tissue biopsy versus bone scintigraphy. Results There were 1,069 patients with ATTRwt amyloidosis and 525 with ATTRv amyloidosis with cardiac mutations enrolled in THAOS. The median time from symptom onset to ATTRwt amyloidosis diagnosis did not change over the past 5 years (>60 months from 2015–2019). ATTRwt amyloidosis diagnoses increased from 2 in 2005 to >100 per year from 2016, with a more pronounced increase in the United States compared with the rest of the world. Diagnoses of ATTRwt amyloidosis by tissue biopsy increased yearly and peaked in 2014 before declining, whereas diagnoses by bone scintigraphy increased markedly since 2011. ATTRv amyloidosis with cardiac mutation diagnoses increased from 3 in 2005 to 37 in 2011, then plateaued. The proportion of patients with ATTRwt amyloidosis diagnosed with New York Heart Association functional class III/IV heart failure decreased from 2012 (46.4%) to 2019 (16.0%). Conclusions In the past decade, ATTRwt amyloidosis diagnoses increased worldwide. Despite the growing utilization of bone scintigraphy, patients are diagnosed several years after symptom onset. (Transthyretin Amyloidosis Outcomes Survey [THAOS]; NCT00628745 )
The intracellular Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase (SHP-1) has been characterized as a negative regulator of T cell function, contributing to the definition of T cell receptor signaling thresholds in developing and peripheral mouse T lymphocytes. The activation of SHP-1 is achieved through the engagement of its tandem SH2 domains by tyrosine-phosphorylated proteins; however, the identity of the activating ligand(s) for SHP-1, within mouse primary T cells, is presently unresolved. The identification of SHP-1 ligand(s) in primary T cells would provide crucial insight into the molecular mechanisms by which SHP-1 contributes to in vivo thresholds for T cell activation. Here we present a combination of biochemical and yeast genetic analyses indicating CD22 to be a T cell ligand for the SHP-1 SH2 domains. Based on these observations we have confirmed that CD22 is indeed expressed on mouse primary T cells and capable of associating with SHP-1. Significantly, CD22-deficient T cells demonstrate enhanced proliferation in response to anti-CD3 or allogeneic stimulation. Furthermore, the co-engagement of CD3 and CD22 results in a raising of TCR signaling thresholds hence demonstrating a previously unsuspected functional role for CD22 in primary T cells. SHP-1,1 an intracellular protein-tyrosine phosphatase, has been demonstrated to be a negative regulator of TCR signaling thresholds (1). SHP-1 is normally maintained in a catalytically inactive state whereby activation minimally requires the engagement of the amino-terminal SH2 domain of SHP-1 by phosphotyrosine (PY)-containing ligand (2, 3). It is predicted that SHP-1-activating ligand(s) exists on mouse naïve T cells based on substantial functional evidence indicating SHP-1 to be catalytically active in naïve T cells (1, 4 -8). It is currently assumed that SHP-1 is activated by one or more components of the TCR signaling pathway. Indeed, the intracellular proteintyrosine kinase, ZAP-70, has been proposed to bind SHP-1 (9).However, the best evidence of SHP-1-associating molecules in other hemopoietic cells relates to the family of immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptors (10). In particular, ITIM receptors Ly49 and CD66a associate with SHP-1 in subpopulations of primary T cells, but to date there has been no definition of the ITIM receptors that activate SHP-1 in the majority of mouse primary T cells (11).In the first instance, we have exploited SHP-1-deficient moth-eaten T cells to assist in the definition of genuine associations between SHP-1 and TCR signaling components in CD3/TCR-stimulated mouse primary T cells. Our results reveal no binding of the CD3 invariant chains or ZAP-70 to SHP-1 in mouse primary T cells following TCR/CD3 ligation. However, by employing pervanadate (PV) to induce a robust tyrosine phosphorylation of cellular proteins in primary T cells, we demonstrated that a glycosylated tyrosyl phosphoprotein of 150 kDa, (pp150) associates with SHP-1 in mouse peripheral T cells. We have ident...
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