bims-proreb 2025-12-28 papers

Issue of 2025–12–28
four papers selected by
Shayan Motiei, Universität des Saarlandes

Cells. 2025 Dec 12. pii: 1976. [Epub ahead of print]14(24):

Maintenance and Decline of Neuronal Lysosomal Function in Aging.

Lysosomes are central effectors of cellular maintenance, integrating the degradation of damaged organelles and protein aggregates with macromolecule recycling and metabolic signaling. In neurons, lysosomes are particularly crucial due to the cells' long lifespan, polarized architecture, and high metabolic demands. Proper regulation of lysosomal function is essential to sustain proteostasis, membrane turnover, and synaptic integrity. Although lysosomal dysfunction has been extensively studied in neurodegenerative diseases, far less is known about how lysosomal capacity and function are maintained-or fail to be maintained-with age in non-diseased neurons. In this review, we summarize current understanding of neuronal lysosomal dynamics, discuss methodological challenges in assessing lysosomal capacity and function, and highlight recent advances that reveal age-associated decline in neuronal lysosomal competence.

Keywords: TFEB; aging; autolysosome; autophagy; endolysosome; lysosome; neuron

DOI: https://doi.org/10.3390/cells14241976

J Bacteriol. 2025 Dec 23. e0036025

The gram-positive HtrA, the protease that is also a chaperone.

Sarah Latimer, Charles Agbavor, Laty A Cahoon.

High-temperature requirement A (HtrA) aids in protein homeostasis by playing a key dual role as a chaperone and protease. HtrA ensures protein folding quality control during secretion and protects cells against protein aggregation by degrading misfolded proteins. HtrA proteins are typically composed of a protease domain and at least one PDZ domain, proposed to help regulate their activity and interactions with substrates. In gram-positive bacteria, HtrA contributes to critical cellular functions and has been linked to processes such as maintaining envelope integrity, stress resistance, and virulence. In addition, HtrA has been shown to contribute to the modulation of competence and biofilm dynamics as well as the degradation of host proteins in infection models. In some gram-positive bacteria, HtrA expression is regulated by two-component systems, but many HtrA upstream signals and downstream targets remain unclear. As antibiotic resistance continues to rise, HtrA is gaining attention as a promising target of inhibition for new antibacterial strategies. However, a lack of structural information, unclear regulatory mechanisms, and unknown substrates make designing effective HtrA inhibitors challenging. This review highlights these knowledge gaps and aims to spark more focused research on HtrA in gram-positive species.

Keywords: HtrA; chaperone; gram-positive bacteria; secretion; serine protease

DOI: https://doi.org/10.1128/jb.00360-25

bioRxiv. 2025 Dec 18. pii: 2025.12.17.689083. [Epub ahead of print]

UV induces common cutaneous amyloid-like melanosomal protein aggregates.

Misfolding of aggregation-prone proteins underpins diseases known as proteinopathies. One of these proteins, alpha-synuclein, is a component of aggregates in neurodegenerative conditions such as Parkinson's disease. The melanosomal protein PMEL, which forms physiologic amyloid scaffold structures on which melanin is organized in melanosomes, similarly ectopically accumulates in the dermis in many forms of cutaneous hyperpigmentation. Here, we demonstrate in a wide range of common clinical pigmentary disorders, as well as in primary melanocyte and mouse models examined by molecular, proteomic, and electron microscopic tools, that melanocytic alpha-synuclein is a prominent component of intracellular protein aggregates bound to similar proteins as in Parkinson's disease, as well as melanized extracellular protein deposits. Using the Real Time Quaking-Induced Conversion Assay (RT-QuIC), we demonstrate that UV induces misfolded melanosomal proteins to self-propagate, augmenting this pathology in prion-like fashion. CUT&RUN chromatin profiling and single-cell RNA-seq demonstrate that melanocytes utilize microphthalmia-associated transcription factor (MITF)-regulated autophagy to counteract protein aggregation, identifying aggregate removal as a core function of tanning. In contrast to extracellular aggregation, impaired intracellular aggregate removal contributes to melanocyte senescence, which conversely exacerbates chronic hypopigmentation and photoaging-related discoloration. These findings identify melanosomal proteinopathy as a common contributor to melanocyte dysfunction and suggest aggregate-focused management approaches.

DOI: https://doi.org/10.64898/2025.12.17.689083

bioRxiv. 2025 Dec 15. pii: 2025.12.12.694052. [Epub ahead of print]

Proteostasis Remodeling Across Development Defines Fetal, Neonatal, and Adult Hematopoietic Stem Cell States.

Helena Yu, Yoon Joon Kim, Katelyn Chen, Andrea Z Liu, Mary Jean Sunshine, Robert A J Signer.

Hematopoietic stem cells (HSCs) must preserve protein homeostasis (proteostasis) despite dramatic changes in proliferative and biosynthetic demands during development, yet how proteostasis is regulated across these transitions is poorly understood. Here, we show that fetal and neonatal HSCs operate through distinct, stage-specific proteostasis programs that differ fundamentally from those in adulthood. Using quantitative in vivo assays spanning embryonic through adult stages, we uncover an unanticipated decoupling between protein synthesis and protein quality control during development, revealing that fetal and neonatal HSCs employ specialized mechanisms to safeguard proteome integrity under developmental stress. Developing HSCs experience a distinctive proteostasis landscape characterized by elevated protein synthesis, increased unfolded protein burden, and selective engagement of stress-buffering and protein degradation pathways that are largely dispensable in young adult HSCs. Disruption of these pathways compromises early life HSC function and long-term fitness, establishing proteostasis control as a key regulator of stem cell maturation. These findings define previously unrecognized mechanisms by which HSCs manage the proteome during early life and reveal fundamental principles governing stem cell proteostasis across ontogeny.

DOI: https://doi.org/10.64898/2025.12.12.694052