bims-unfpre 2025-06-01 papers

Issue of 2025–06–01
five papers selected by
Susan Logue, University of Manitoba

Blood. 2025 May 28. pii: blood.2024027846. [Epub ahead of print]

PERK Maintains Hematopoietic Stem Cell Pool Integrity under Endoplasmic Reticulum Stress by Promoting Proliferation.

Manxi Zheng, Qinlu Peng, Erin M Kropp, Zhejuan Shen, Suxuan Liu, Zhengyou Yin, Sho Matono, Takao Iwawaki, Xiang Wang, Ken Inoki, Yang Mei, Qing Li, Lu Liu.

The integrity of the hematopoietic stem cell (HSC) pool depends on effective long-term self-renewal and the timely elimination of damaged or differentiation-prone HSCs. While the PERK branch of the unfolded protein response (UPR) has been shown to initiate pro-apoptotic signaling in response to ER stress in vitro, its role in regulating HSC fate in vivo remains incompletely understood. Here, we demonstrate that PERK is dispensable for steady-state hematopoiesis and HSC self-renewal under homeostatic conditions. However, under ER stress induced by disruption of ER-associated degradation (ERAD), via knockout of key components such as Sel1L or Hrd1, PERK becomes activated and drives HSC proliferation and depletion. Notably, deletion of PERK or expression of a kinase-dead PERK mutant significantly rescues the HSC defects caused by Sel1L or Hrd1 loss. Mechanistically, ERAD deficiency does not lead to increased HSC apoptosis or elevated reactive oxygen species (ROS), and PERK knockout has minimal impact on HSC apoptosis. Instead, PERK activation promotes aberrant mTOR signaling and HSC hyperproliferation, ultimately compromising self-renewal capacity. This PERK-driven elimination of stressed HSCs may function as a protective mechanism to maintain overall HSC pool integrity. Collectively, our findings reveal a previously unrecognized, proliferative, and apoptosis-independent role for PERK in regulating HSC fate under ER stress, highlighting a novel mechanism for preserving HSC homeostasis.

DOI: https://doi.org/10.1182/blood.2024027846

J Biol Chem. 2025 May 22. pii: S0021-9258(25)02133-7. [Epub ahead of print] 110283

The ER-associated Degradation Adaptor SEL1L is Dispensable for ER Homeostasis and the Differentiation of Spermatogenic Cells.

Nusrat Jahan Tushi, Zhibing Zhang, Shengyi Sun.

The SEL1L-HRD1 complex is a critical component of the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway, essential for maintaining ER homeostasis and cellular function. While the crucial roles of SEL1L and HRD1 in various physiological processes have been reported in mice and humans, their specific functions in male germ cells remain unexplored. Here, we show that, while SEL1L is highly expressed in spermatogenic cells, it is dispensable for their differentiation and ER homeostasis. SEL1L deletion in these cells does not affect sperm count, motility, male fertility, or testicular histology. Mechanistically, our data show that SEL1L loss reduces HRD1 protein levels in spermatids but unexpectedly, not in spermatocytes. Furthermore, SEL1L deficiency does not induce overt ER stress response, ER dilation, or cell death in the testes. Collectively, these findings indicate that SEL1L is not required for ER homeostasis or the differentiation of male germ cells.

Keywords: ER stress; ERAD; SEL1L; endoplasmic reticulum; sperm; spermatogenesis; spermiogenesis

DOI: https://doi.org/10.1016/j.jbc.2025.110283

Cell Death Discov. 2025 May 27. 11(1): 254

CO confers neuroprotection via activating the PERK-calcineurin pathway and inhibiting necroptosis.

Jeongmin Park, LiHua Jin, Hyun-Chul Song, Yingqing Chen, Eun Young Jang, Gyu Hwan Park, Chae Ha Yang, Stefan W Ryter, Jeong Woo Park, Min Zheng, Yeonsoo Joe, Hun Taeg Chung.

Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), are marked by progressive neuronal loss. Regulated cell death programs (i.e., necroptosis) as well as homeostatic mechanisms (i.e., autophagy) can modulate disease pathogenesis. Low-dose carbon monoxide (CO) has been shown to activate cytoprotective responses in various models of tissue injury. Our study investigates the protective roles of CO in neurodegenerative disease through the modulation of necroptosis and autophagy programs. We found that CO activates the Protein kinase RNA (PKR)-like ER kinase (PERK) branch of the unfolded protein response (UPR) and the calcineurin pathway, leading to significant neuroprotective effects in cellular and mouse models of PD. CO-induced PERK activation promotes the nuclear translocation of transcription factor EB (TFEB). Subsequently, TFEB enhances autophagy through increased expression of autophagy-related genes and inhibits necroptosis by suppressing the phosphorylation and oligomerization of Mixed Lineage Kinase Domain-Like Pseudokinase (MLKL), a key necroptosis regulator. Furthermore, CO enhances the expression of Beclin 1, which inhibits necroptosis, independently of its autophagic function, by regulating MLKL oligomerization. Our findings suggest that modulation of the PERK-calcineurin pathway and downstream activation of cellular defense mechanisms by CO may serve as a promising therapeutic approach to mitigate neuronal loss in neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41420-025-02530-9

Nat Commun. 2025 May 25. 16(1): 4855

Palbociclib and dsRNA sensor co-operate to enhance anti-cancer effects through ER stress and modulation of immune evasion.

Cytoplasmic pattern recognition receptors (PRR) for double-stranded RNA, such as RIG-I/MDA5, are key mediators of anti-viral responses. Here we screen for synergistic drug-virotherapy combinations and find that the reovirus type III Dearing strain (Rt3D)-palbociclib combination augments oncolytic virus-induced stress responses and increases interferon production and signaling. Data from RIG-I agonist and ER stress-inducing agents further confirms the crosstalk between RNA-sensing and ER stress in inducing cancer cell death and interferon production. Combined Rt3D-palbociclib also increases innate immune activation and IFN-induced HLA expression within tumor cells, with accompanying alterations in the epigenetic landscape and endogenous retroviral (ERV) elements. Analysis of the immunopeptidome in treated cells further reveals changes to HLA-captured peptides, including altered expression of peptides from cancer or testis antigens and ERVs. Our findings thus highlight the crosstalk between stress signaling and PRR activation for mediating enhanced anti-cancer efficacy.

DOI: https://doi.org/10.1038/s41467-025-60133-5

Autophagy. 2025 May 25.

Endoplasmic reticulum tubule junctions are sites of autophagy.

Susan Ferro-Novick.

Selective endoplasmic reticulum (ER) macroautophagy/autophagy, also called reticulophagy, is a disposal pathway that degrades ER domains. A major role of reticulophagy is the removal of ER domains that contain misfolded proteins resistant to ER-associated degradation (ERAD). Our studies have shown that RTN3L, the SEC24C-SEC23 COPII coat subcomplex, and the CUL3KLHL12 E3 ligase that ubiquitinates RTN3L targets ERAD-resistant misfolded protein condensates for degradation at ER-reticulophagy sites (ERPHS), autophagic sites that form at tubule junctions. Unexpectedly, we found that the Parkinson disease protein PINK1 regulates ER tubulation. Loss of PINK1 disrupts the formation of peripheral tubule junctions, and, as a consequence, reticulophagy is blocked and misfolded proteins accumulate in the ER. Overexpression of the ER tubulating domain of DNM1L/DRP1, a multifunctional PINK1 kinase substrate that localizes to ER-mitochondria contact sites, increases junctions and restores reticulophagy. Our findings show that PINK1 shapes the ER to target misfolded proteins for RTN3L-SEC24C-mediated macroreticulophagy at defined ER sites, peripheral tubule junctions.

Keywords: ER junctions; ER quality control; Reticulophagy

DOI: https://doi.org/10.1080/15548627.2025.2508934