Biology subjects

Rosenblum, J.

Publications and source records attributed to Rosenblum, J..

3 recordsLinked to original sources

bioRxiv2026

Structural survey of HIF-2α reveals regulation of its subcellular localization and protein interactome

Hypoxia-inducible factor 2 (HIF-2) is a central regulator of cellular homeostasis and a known oncogenic driver in multiple cancers. Although HIF-2 is canonically defined as a nuclear transcription factor, its cytoplasmic presence and non-canonical functions remain poorly understood. Here, we performed a structural survey of HIF-2 to determine the mechanisms underlying subcellular localization, protein abundance, and activity using a deletion-construct library, transcriptional assays, and in vivo xenograft models. We found that the oxygen-dependent degradation domain (ODD), the N-terminal intrinsically disordered region (n-IDR) and the N-terminal transactivation domain (NTAD) promote cytoplasmic localization, whereas the C-terminal IDR drives nuclear accumulation. Surprisingly, we found that HIF-2 nuclear localization occurs also in the absence of PAS A and B, the domains required for ARNT (HIF-1{beta}) dimerization, resolving the long-standing question in the field. These data suggest a dominant role for non-canonical cytoplasmic mechanisms in HIF-2-driven tumorigenesis. Strikingly, neither NTAD nor the C-terminal CTAD was required for tumor growth in vivo, in coherence with our transcriptional assays indicating that CTAD is dispensable for transactivation and NTAD functions as a suppressor rather than an activator of transcription. Proteomic analyses reveal HIF-2 interactions with regulators of mitochondrial function, translation initiation, RNA splicing, vesicular transport, and DNA replication. Together, these findings uncover previously unrecognized structural and functional complexity of HIF-2 compartmentalization and expand its role beyond canonical transcriptional regulation.

cell biology↗

bioRxiv2025

Lipid transport is necessary for neocortical lamination

We previously described the Alkuraya-Ku[c]inskas syndrome, a disorder associated with biallelic variants in BLTP1 (bridge-like lipid transfer protein), a.k.a. KIAA1109. The majority of probands die perinatally with corpus callosum agenesis, ventriculomegaly and arthrogryposis. Homozygous ablation of mouse Bltp1 resulted in similar preweaning lethality. Here, we describe ten novel patients expanding the characterization of this syndrome at the mild end of the phenotypic spectrum. To model this syndrome, we engineered Emx1-Cre-mediated conditional knockouts (cKO) in which Bltp1 expression is only removed in cortical and hippocampal neurons. This restricted ablation of Bltp1 recapitulated the preweaning lethality observed in the constitutional knockouts, suggesting that lack of BLTP1 expression in neurons is sufficient to cause death. Homozygous cKO presented a complete agenesis of the corpus callosum, a smaller anterior commissure, a malformed hippocampus and a reduced thickness of the cortical plate with a complete lack of defined structural layers and absence of radial glial and intermediate neural progenitors and mature neurons. As BLTP1 was shown to be a barrel-shaped tube containing lipids, we compared the amount of lipid species in the cKO and their control littermates cortexes. We observed significant depletions of ether-linked phosphatidylethanolamines and triglycerides and accumulations of sphingomyelins and hexosylceramides in cKOs. Our results are consistent with the recent description of BLTP1 as a tubular protein that transports phospholipids between the endoplasmic reticulum and the plasma membrane. They suggest that non-vesicular lipid transport is essential for neocortical and cerebellar lamination. Consistent with a BLTP1 role in cortex development we show that heterozygous carriers of a BLTP1 truncation variant presented a decrease in peripheral cortical grey matter suggesting an autosomal dominant inheritance pattern beside the already described autosomal recessive.

genetics↗

bioRxiv2024

SECRET-GWAS: Confidential Computing for Population-Scale GWAS

Genomic data from a single institution lacks global diversity representation, especially for rare variants and diseases. Confidential computing can enable collaborative GWAS without compromising privacy or accuracy, however, due to limited secure memory space and performance overheads previous solutions fail to support widely used regression methods. We present SECRET-GWAS: a rapid, privacy-preserving, population-scale, collaborative GWAS tool. We discuss several system optimizations, including streaming, batching, data parallelization, and reducing trusted hardware overheads to efficiently scale linear and logistic regression to over a thousand processor cores on an Intel SGX-based cloud platform. In addition, we protect SECRET-GWAS against several hardware side-channel attacks, including Spectre, using data-oblivious code transformations and optimized speculative load hardening. SECRET-GWAS is an open-source tool and works with the widely used Hail genomic analysis framework. Our experiments on Azures Confidential Computing platform demonstrate that SECRET-GWAS enables multivariate linear and logistic regression GWAS queries on population-scale datasets (one million patients, four million SNPs, 12 covariates) from ten independent sources in just 4.5 and 29 minutes, respectively.

bioinformatics↗