Beyond Good and Evil: Formalizing the Security Guarantees of Compartmentalizing Compilation

Compartmentalization is good security-engineering practice. By breaking a large software system into mutually distrustful components that run with minimal privileges, restricting their interactions to conform to well-defined interfaces, we can limit the damage caused by low-level attacks such as control-flow hijacking. When used to defend against such attacks, compartmentalization is often implemented cooperatively by a compiler and a low-level compartmentalization mechanism. However, the formal guarantees provided by such compartmentalizing compilation have seen surprisingly little investigation. We propose a new security property, secure compartmentalizing compilation (SCC), that formally characterizes the guarantees provided by compartmentalizing compilation and clarifies its attacker model. We reconstruct our property by starting from the well-established notion of fully abstract compilation, then identifying and lifting three important limitations that make standard full abstraction unsuitable for compartmentalization. The connection to full abstraction allows us to prove SCC by adapting established proof techniques; we illustrate this with a compiler from a simple unsafe imperative language with procedures to a compartmentalized abstract machine.Comment: Nit

Retrograde trafficking of Argonaute 2 acts as a rate-limiting step for de novo miRNP formation on endoplasmic reticulum–attached polysomes in mammalian cells

microRNAs are short regulatory RNAs in metazoan cells. Regulation of miRNA activity and abundance is evident in human cells where availability of target messages can influence miRNA biogenesis by augmenting the Dicer1-dependent processing of precursors to mature microRNAs. Requirement of subcellular compartmentalization of Ago2, the key component of miRNA repression machineries, for the controlled biogenesis of miRNPs is reported here. The process predominantly happens on the polysomes attached with the endoplasmic reticulum for which the subcellular Ago2 trafficking is found to be essential. Mitochondrial tethering of endoplasmic reticulum and its interaction with endosomes controls Ago2 availability. In cells with depolarized mitochondria, miRNA biogenesis gets impaired, which results in lowering of de novo–formed mature miRNA levels and accumulation of miRNA-free Ago2 on endosomes that fails to interact with Dicer1 and to traffic back to endoplasmic reticulum for de novo miRNA loading. Thus, mitochondria by sensing the cellular context regulates Ago2 trafficking at the subcellular level, which acts as a rate-limiting step in miRNA biogenesis process in mammalian cells

Lipid raft microdomain compartmentalization of TC10 is required for insulin signaling and GLUT4 translocation.

Recent studies indicate that insulin stimulation of glucose transporter (GLUT)4 translocation requires at least two distinct insulin receptor-mediated signals: one leading to the activation of phosphatidylinositol 3 (PI-3) kinase and the other to the activation of the small GTP binding protein TC10. We now demonstrate that TC10 is processed through the secretory membrane trafficking system and localizes to caveolin-enriched lipid raft microdomains. Although insulin activated the wild-type TC10 protein and a TC10/H-Ras chimera that were targeted to lipid raft microdomains, it was unable to activate a TC10/K-Ras chimera that was directed to the nonlipid raft domains. Similarly, only the lipid raft-localized TC10/ H-Ras chimera inhibited GLUT4 translocation, whereas the TC10/K-Ras chimera showed no significant inhibitory activity. Furthermore, disruption of lipid raft microdomains by expression of a dominant-interfering caveolin 3 mutant (Cav3/DGV) inhibited the insulin stimulation of GLUT4 translocation and TC10 lipid raft localization and activation without affecting PI-3 kinase signaling. These data demonstrate that the insulin stimulation of GLUT4 translocation in adipocytes requires the spatial separation and distinct compartmentalization of the PI-3 kinase and TC10 signaling pathways

Functional compartmentalization of Rad9 and Hus1 reveals diverse assembly of the 9-1-1 complex components during the DNA damage response in Leishmania

The Rad9-Rad1-Hus1 (9-1-1) complex is a key component in the coordination of DNA damage sensing, cell cycle progression and DNA repair pathways in eukaryotic cells. This PCNA-related trimer is loaded onto RPA-coated single stranded DNA and interacts with ATR kinase to mediate effective checkpoint signaling to halt the cell cycle and to promote DNA repair. Beyond these core activities, mounting evidence suggests that a broader range of functions can be provided by 9-1-1 structural diversification. The protozoan parasite Leishmania is an early-branching eukaryote with a remarkably plastic genome, which hints at peculiar genome maintenance mechanisms. Here, we investigated the existence of homologs of the 9-1-1 complex subunits in L. major and found that LmRad9 and LmRad1 associate with chromatin in response to replication stress and form a complex in vivo with LmHus1. Similar to LmHus1, LmRad9 participates in telomere homeostasis and in the response to both replication stress and double strand breaks. However, LmRad9 and LmHus1-deficient cells present markedly opposite phenotypes, which suggest their functional compartmentalization. We show that some of the cellular pool of LmRad9 forms an alternative complex and that some of LmHus1 exists as a monomer. We propose that the diverse assembly of the Leishmania 9-1-1 subunits mediates functional compartmentalization, which has a direct impact on the response to genotoxic stress

The Long and Viscous Road: Uncovering Nuclear Diffusion Barriers in Closed Mitosis

During Saccharomyces cerevisiae closed mitosis, parental identity is sustained by the asymmetric segregation of ageing factors. Such asymmetry has been hypothesized to occur via diffusion barriers, constraining protein lateral exchange in cellular membranes. Diffusion barriers have been extensively studied in the plasma membrane, but their identity and organization within the nucleus remain unknown. Here, we propose how sphingolipid domains, protein rings, and morphological changes of the nucleus may coordinate to restrict protein exchange between nuclear lobes. Our spatial stochastic model is based on several lines of experimental evidence and predicts that, while a sphingolipid domain and a protein ring could constitute the barrier during early anaphase; a sphingolipid domain spanning the bridge between lobes during late anaphase would be entirely sufficient. Additionally, we explore the structural organization of plausible diffusion barriers. Our work shows how nuclear diffusion barriers in closed mitosis may be emergent properties of simple nanoscale biophysical interactions.Comment: 21 pages, 6 figures and supplementary material (including 8 additional figures and a Table

Horizontal transfer between loose compartments stabilizes replication of fragmented ribozymes

The emergence of replicases that can replicate themselves is a central issue in the origin of life. Recent experiments suggest that such replicases can be realized if an RNA polymerase ribozyme is divided into fragments short enough to be replicable by the ribozyme and if these fragments self-assemble into a functional ribozyme. However, the continued self-replication of such replicases requires that the production of every essential fragment be balanced and sustained. Here, we use mathematical modeling to investigate whether and under what conditions fragmented replicases achieve continued self-replication. We first show that under a simple batch condition, the replicases fail to display continued self-replication owing to positive feedback inherent in these replicases. This positive feedback inevitably biases replication toward a subset of fragments, so that the replicases eventually fail to sustain the production of all essential fragments. We then show that this inherent instability can be resolved by small rates of random content exchange between loose compartments (i.e., horizontal transfer). In this case, the balanced production of all fragments is achieved through negative frequency-dependent selection operating in the population dynamics of compartments. This selection mechanism arises from an interaction mediated by horizontal transfer between intracellular and intercellular symmetry breaking. The horizontal transfer also ensures the presence of all essential fragments in each compartment, sustaining self-replication. Taken together, our results underline compartmentalization and horizontal transfer in the origin of the first self-replicating replicases.Comment: 14 pages, 4 figures, and supplemental materia