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PH Gradient Drives Redox Reactions in the Nucleolar Caps to Modulate Nucleolar Integrity and Function

ABSTRACT: Enzymatic catalysis has long been thought of as the primary driver of redox processes in living cells. Biomolecular condensates, formed via phase separation, exhibit unique physicochemical properties that distinguish them from the surrounding milieu. Emerging evidence indicates that the electrochemical properties of biomolecular condensates can participate in a plethora of pathophysiological processes by potentiating chemical reactions, including redox reactions. Nevertheless, the regulatory mechanisms governing the electrochemical equilibrium of biomolecular condensates and their influence on the emergent physicochemical functions, especially in cellulo, remain poorly understood. Here, we demonstrate that specific nucleolar stressors induce the formation of highly alkaline nucleolar caps, which generate an interfacial pH gradient that drives spontaneous redox reactions. Non-enzymatic reactive oxygen species (ROS) production depends on positively charged constituents within the nucleolar caps and correlates strongly with the pH microenvironment. Excessive ROS accumulation directly modulates the partition and diffusion of proteins rich in cysteine and methionine, whereas scavenging ROS markedly accelerates the recovery of nucleolar multiphase organization and functionality upon stress removal. Collectively, our findings propose a non-enzymatic redox mechanism operating within cellular condensates and highlight the critical role of physical interfaces in orchestrating the chemical dynamics of biomolecular condensates.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328521 | GEO | 2026/04/25

REPOSITORIES: GEO

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Project description:Biomolecular condensates are implicated in many cellular processes, and are thought to create subcellular microenvironments that regulate specific biochemical activities 1-7. For example, in vitro experiments suggest that condensates enable non-stochiometric enrichment of small molecules within condensates 8-12. However, probing the microenvironments of condensates in cells is a major challenge, because tools to selectively manipulate specific condensates in living cells are limited. Here we developed a non-natural micropeptide (i.e., the “killswitch”) and a Nanobody-based recruitment system as a universal approach to probe endogenous condensates, and demonstrate direct links between condensate microenvironments and function in cells. The killswitch is a hydrophobic, aromatic-rich sequence with an ability to self-associate, and no homology to human proteins. When recruited to endogenous and disease-specific condensates in human cells, the killswitch arrested the dynamics of the condensate-forming proteins, which led to predicted and unexpected effects. Targeting the killswitch to the nucleolar protein NPM1 altered nucleolar composition, and inhibited the dynamics of a ribosomal protein within nucleoli. Targeting the killswitch to fusion oncoprotein condensates inhibited the dynamics of effector proteins in the condensates, altered condensate composition, and inhibited proliferation of condensate-driven leukemia cells. In adenoviral nuclear condensates, the killswitch inhibited partitioning of capsid protein into condensates, and suppressed viral particle assembly. The results suggest that the microenvironment within cellular condensates has an essential contribution to non-stochiometric enrichment and the dynamics of effector proteins. The killswitch is a widely applicable tool to alter the material properties of endogenous condensates, and as a consequence, to probe functions of condensates linked to diverse physiological and pathological processes in living systems.

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PH Gradient Drives Redox Reactions in the Nucleolar Caps to Modulate Nucleolar Integrity and Function

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