bims-proreb 2026-01-18 papers

Issue of 2026–01–18
three papers selected by
Shayan Motiei, Universität des Saarlandes

bioRxiv. 2026 Jan 09. pii: 2026.01.08.698479. [Epub ahead of print]

A non-canonical role for UPR ER during heat stress in C. elegans.

Athena Alcala, Toni Castro Torres, Rebecca Aviles Barahona, Phillip A Frankino, Ryo Higuchi-Sanabria, Gilberto Garcia.

Organisms rely on coordinated stress responses to maintain cellular homeostasis. Perhaps the best-known example of multiple stress inputs converging onto a single response is the integrated stress response (ISR), which reduces global translation under various stress conditions to reduce the protein folding burden of the cell. Similarly, most stress responses generally involve coordination of additional protein homeostasis (proteostasis) pathways, including increased expression of chaperones to refold proteins, as well as activation of clearance mechanisms, such as autophagy and the ubiquitin proteosome system. Our study investigates how heat stress can influence coordinated activation of both cytosolic and ER chaperones, exploring bidirectional cross talk between canonical activators of the cytosolic heat-shock response (HSR) and the unfolded protein response of the ER (UPR ER ). Using robust transcriptional reporters in the C. elegans model system, we explore a non-canonical activation of the UPR ER under heat stress by the coordinated effects of XBP-1 and HSF-1. We further investigate inter tissue communications of stress whereby neuronal or glial activation of the UPR ER can result in heterotypic enhancement of the HSR in peripheral and can increase thermotolerance. This work highlights the complex convergence of cellular stress responses, a phenomenon that may reflect a general strategy wherein localized stress can activate numerous proteostasis pathways to prevent whole cell and whole organism damage.
Article Summary: A reductionist approach to studying cellular stress responses is critical for dissecting specific molecular and genetic drivers of stress response. However, stress responses are often convergent and overlapping, and these single input and output studies may miss their complex interplay. Many studies have revealed the intricate coordination of stress responses, including the ability of seemingly organelle-specific stress responses, like mitochondrial stress responses, to directly influence cytosolic and ER health. Our study adds to this growing field by describing a unique, bidirectional crosstalk between the cytosolic and ER stress pathways, highlighting systemic coordination of stress resilience.

DOI: https://doi.org/10.64898/2026.01.08.698479

Genetics. 2026 Jan 13. pii: iyag007. [Epub ahead of print]

The Ubiquitin-Proteasome Pathway Mediates Selective Degradation of Unloaded Argonaute Proteins in C. elegans.

Jenny M Zhao, Dieu An H Nguyen, Diego Cervantes, Brandon Vong, Carolyn M Phillips.

Argonaute proteins are essential effectors of small RNA-mediated gene regulation, yet the extent to which their stability depends on small RNA loading remains poorly understood. In Caenorhabditis elegans, we systematically disrupted the small RNA binding capacity of multiple Argonaute proteins to assess their stability in the absence of small RNA partners. We found that while most Argonautes remain stable when unable to bind small RNAs, a subset, including PRG-1, HRDE-1, and PPW-2, exhibited markedly reduced protein levels. Focusing on the PIWI-clade Argonaute PRG-1, we show that its destabilization occurs post-translationally and is independent of mRNA expression or translational efficiency. Instead, unbound PRG-1 is targeted for degradation by the ubiquitin-proteasome system. Additionally, the failure to load piRNAs disrupts PRG-1 localization to perinuclear germ granules. We further identify the E3 ubiquitin ligase EEL-1 as a factor contributing to the degradation of unloaded PRG-1. These findings uncover a critical role for small RNA loading in maintaining the stability and localization of a subset of Argonaute proteins, and reveal a quality control mechanism that selectively eliminates unbound PRG-1 to preserve germline regulatory fidelity.

DOI: https://doi.org/10.1093/genetics/iyag007

Proc Natl Acad Sci U S A. 2026 Jan 20. 123(3): e2529422123

Proteasomal proteolysis in p62 condensates directs tumor suppression or growth depending on their subcellular localization.

Chen Lulu-Shimron, Zhiwen Luo, Vera Brekhman, Lina Huang, Ido Livneh, Hidetaka Kosako, Victoria Cohen-Kaplan, Aaron Ciechanover.

p62/SQSTM1 generates liquid-liquid phase-separated condensates that participate in diverse processes, including protein quality control (PQC) and autophagy. Nuclear p62 condensates were shown to act as ubiquitin- and proteasome-mediated degradation hubs, whereas the involvement of cytoplasmic condensates in this pathway has remained unclear. Here, we show that cytoplasmic p62 condensates serve as a hub for proteasomal degradation that displays distinct substrate preferences compared with nuclear condensates. Specifically, cytoplasmic condensates mediate accelerated degradation of the tumor suppressor p53 through recruitment MDM2, its E3 ligase, while nuclear condensates are selectively enriched with USP7, a deubiquitinating enzyme (DUB) that stabilizes p53. Immunohistochemical analysis of human tissues reveal that p62 in healthy tissues is largely localized to the nucleus, whereas in the corresponding malignant tissues, it is largely in the cytosol, which is correlated with reduced p53 abundance in tumors. Nuclear p62 condensates also promote the degradation of oncogenic c-Myc, underscoring compartment-specific differences in protein turnover. Experiments in cancer cells and xenografts demonstrate that cytoplasmic p62 condensates drive tumor growth, whereas nuclear p62 condensates suppress it. Moreover, condensate formation rather than p62 expression alone is required for both enhanced proteolytic activity and tumor growth modulation. Proteomic analysis reveals that nuclear p62, unlike its cytosolic counterpart, is linked to enrichment of proteins associated with apoptosis, p53 stabilization, DNA damage response, and cellular senescence-all related to tumor suppression. These findings establish that p62 condensates provide compartment-specific regulation of ubiquitin and proteasomal degradation and suggest that manipulating their localization or affecting their dynamics can offer different therapeutic opportunities.

Keywords: c-Myc; cancer; p53; p62 condensates; ubiquitin–proteasome system

DOI: https://doi.org/10.1073/pnas.2529422123