Biology subjects

Curran, J. A.

Publications and source records attributed to Curran, J. A..

5 recordsLinked to original sources

bioRxiv2026

The microprotein SEP53BP1: its bizarre mode of translational expression and intracellular behaviour.

Microproteins are proteins of <100 amino acids. They represent a major, and until recently, overlooked fraction of the human proteome. However, it has now been demonstrated that many of these proteins play key roles in cellular physiology. Our group reported the expression of a microprotein expressed from an ioORF within the 53BP1 CDS arising as a result of delayed translational reinitiation mediated by a small uORF within the 5 TL. We named this microprotein SEP53BP1. We have sought to expand these studies with the ultimate aim of establishing a function for this microprotein. Although this remains elusive, we report findings providing new insights into the elements regulating its translation and demonstrate that the SEP53BP1 sequence serves as a Golgi targeting tag. Lastly, despite the fact that subunits of the proteasome feature prominently on interactome studies we were unable to demonstrate an impact of microprotein over-expression on the activities of both the proteasome and immunoproteasome.

molecular biology↗

bioRxiv2024

Biomathematical enzyme kinetics model of prebiotic autocatalytic RNA networks: degenerating parasite-specific hyperparasite catalysts confer parasite resistance and herald the birth of molecular immunity

Catalysis and specifically autocatalysis are the quintessential building blocks of life. Yet, although autocatalytic networks are necessary, they are not sufficient for the emergence of life-like properties, such as self-propagation (replication) and adaptation. The ultimate and potentially fatal threat faced by molecular replicators is parasitism; if the polymerase error rate exceeds a critical threshold, even the fittest molecular species will disappear. Here we have developed an autocatalytic RNA early life mathematical network model based purely on enzyme kinetics, more specifically the steady-state approximation. We confirm previous models showing that these autocatalytic cycles are sustainable, provided there is a sufficient nucleotide pool. However, molecular parasites arise rapidly and become unsustainable unless they sequentially degenerate to hyperparasites (i.e. parasites of parasites). These hyperparasites acquire parasite binding specificity via two distinct temporal pathways. Our model is supported at three levels; firstly, ribozyme polymerases display Michaelis-Menten saturation kinetics and comply with the steady-state approximation. Secondly, ribozyme polymerases are capable of sustainable auto-amplification and of surmounting the fatal error threshold. Thirdly, with growing sequence divergence of host and parasite catalysts, the probability of self-binding increases and the trend towards cross-reactivity diminishes. Our model predicts that primordial host-RNA populations evolved via an arms race towards a host-parasite-hyperparasite catalyst trio that conferred parasite resistance within an RNA replicator niche. As such, it adds another mechanism - whats more, with biochemical precision - by which parasitism can be tamed and offers an attractive explanation for the universal coexistence of catalyst trios within prokaryotes and the virosphere, heralding the birth of a primitive molecular immunity. Author SummaryThe quintessential components of life comprise a potent mixture of naturally occurring, but improbable chemical reactions (catalysis), and the arrangement of such accelerated chemical reactions into closed loops (autocatalytic sets). This is required, but is not sufficient for such networks to self-propagate (amplification of the information carrier = host polymerization) and adapt (Darwinian evolution). As soon as self-propagation is attained, the next hurdle is parasitism. This typically involves shorter molecules (the products of replicative errors) that hitchhike the replicative potential of the host. They will invariably outcompete the regular amplification process, unless a solution is found. We have addressed this problem using a new model based on the mathematics of catalysis. This model confirms previous studies demonstrating that autocatalytic sets become self-sustaining, assuming that a sufficient pool of molecular building blocks is available. However, molecular parasitism is pervasive and potentially fatal for both host and parasite. In our model, we allow these parasites to degenerate in a controlled fashion, giving rise to parasites of parasites (hyperparasites). As long as these hyperparasites acquire binding specificity for parasites, an attenuation of parasitism is observed. These parasite-hyperparasite cycles stabilize the host cycle, explaining why they are conserved, and why they are the likely reason behind the observation that all cellular hosts are associated with parasites (e.g. bacteria) and hyperparasites (e.g. viruses) across all kingdoms of life. Moreover, it provides a novel solution to the usually intractable problem of parasitism.

evolutionary biology↗

bioRxiv2023

Birth of immunity in early life: stepwise emergence of resistance and immunity to complex molecular parasites via progressively degenerating hyperparasites

Catalysis and specifically autocatalysis are the quintessential building blocks of life. However, autocatalytic networks are necessary but not sufficient for life-like properties such as self-propagation and adaptation to emerge. We previously showed using Lotka-Volterra equations that a tripartite, early life cycle comprising a host-template, molecular parasites and hyperparasites (parasites of parasites) conferred superior stability to the habitat. Here we build on this model, and on the seminal notion that chemical networks and ecologically interacting biological species are akin, implying an instructive equational analogy between catalysis and ecology, both accurately modelled by equations from the Lotka-Volterra family. Template-based autocatalytic RNA networks seed the spontaneous emergence of immunity against molecular parasites, with degenerating molecular parasite catalysts being the founding seed of the homeostatic process. First, upon molecular parasite encounter, specific ribocatalysts providing parasite resistance appear in primordial autocatalytic cycles, supplanted by promiscuous, efficiently self-replicating, but parasite sensitive ribozymes. This is supported by catalyst tradeoff analysis: substrate promiscuity confers high catalytic activity, but entails parasite exposure, higher substrate specificity implies relatively lower activity, yet it offers parasite resistance. Second, sustained parasite influx generates hyperparasite cycles, memorizing parasite-specific catalyst-subunits that now once more provide parasite resistance, in a homeostatically stabilized habitat. Third, under continuous exposure to progressively elaborate parasite populations, hyperparasite catalysts degenerate and embody antiparasite immunity. The observed triggering of microbial immunity by hyperparasitic microbial genomes are in agreement with this model. As such, it offers an attractive and unifying theory for the spontaneous birth of immunity in early life. Author SummaryThe quintessential components of life comprise a potent acceleration of naturally occurring, but improbable chemical reactions (catalysis), and the arrangement of accelerated chemical reactions in closed loops (autocatalytic sets). This is required, but is not sufficient for such networks to self-propagate and adapt. We previously developed an early life model for a stabilized habitat of networks, using a family of equations shown to accurately model both chemical reactions and the interactions of biological species. This model became stabilized only if the molecular host species was parasitized, an event considered unavoidable, and at the same time, the parasite itself was also parasitized. We now built on that model, using the same family of equations, by letting individual autocatalytic sets interact. The new results show that primitive autocatalytic networks emerge spontaneously, but inefficiently and resist parasites. With time, they become more efficient, which renders them parasite-sensitive. Upon continuous external parasite invasion, the primitive, parasite-resistant catalysts (hyperparasites) that still persist are recruited, conferring stability to the habitat. If the habitat is further overwhelmed with parasites, it selects the elegant solution of letting the parasite-resistant catalysts degenerate, which now produces immunity to those parasites ("antibodies"). This represents the birth of adaptive immunity.

evolutionary biology↗

bioRxiv2021

A small protein, derived from an alternative 53BP1 promoter transcript and expressed via translational reinitiation on an internal overlapping ORF, modulates proteasome activity.

The complexity of the metazoan proteome is significantly increased by the expression of small proteins (<100 aas) derived from smORFs within lncRNAs, uORFs, 3 UTRs and, more rarely, reading frames overlapping the CDS. These smORF encoded proteins (SEPs) can have diverse roles, ranging from the regulation of cellular physiological to essential developmental functions. We report the characterisation of a new member of this protein family, SEP53BP1, derived from a small internal ORF that overlaps the CDS that encodes 53BP1. Its expression is coupled to the utilisation of an alternative, cell-type specific, promoter coupled to translational reinitiation events mediated by a uORF in the alternative 5 TL of the mRNA. The uORF-mediated initiation at the internal AUG53BP1 is conserved in metazoan species ranging from human to zebrafish. As such, it couples SEP53BP1 expression to the integrated stress response (ISR). We demonstrate that one function of this protein is to interact with, and stimulate, the activity of the 26S proteasome. As such, it opens the door to new approaches in the treatment of clinical conditions that arise due to the accumulation of toxic intracellular protein aggregates

molecular biology↗

bioRxiv2021

eIF4E3 Forms an Active eIF4F Complex during Stresses (eIF4FS) Targeting mTOR and Re-Programs the Translatome.

The eIF4E are a family of initiation factors that bind the mRNA 5 cap, regulating the proteome and the cellular phenotype. eIF4E1 mediates global translation and its activity is controlled via the PI3K/AKT/mTOR pathway. mTOR down-regulation results in eIF4E1 sequestration into an inactive complex with the 4E binding proteins (4EBPs). The second member, eIF4E2, regulates the translatome during hypoxia. However, the exact function of the third member, eIF4E3, has remained elusive. We have dissected its function using a range of techniques. Starting from the observation that it does not interact with 4EBP1, we demonstrate that eIF4E3 recruitment into an eIF4F complex occurs when Torin1 inhibits the mTOR pathway. Ribo-seq studies demonstrate that this complex (eIF4FS) is translationally active only during stress and that it selects specific mRNA populations based on 5 TL (UTR) length. The interactome reveals that it associates with cellular proteins beyond the cognate initiation factors, suggesting that it may have "moon-lighting" functions. Finally, we provide evidence that cellular metabolism is altered in an eIF4E3 KO background but only upon Torin1 treatment. We propose that eIF4E3 acts as a second branch of the integrated stress response, re-programming the translatome to promote "stress resistance" and adaptation.

molecular biology↗