bims-unfpre 2025-02-16 papers

Issue of 2025–02–16
five papers selected by
Susan Logue, University of Manitoba

eGastroenterology. 2024 Oct;2(4): e100129

Essential roles of the unfolded protein response in intestinal physiology.

Claudio Hetz, Juan Francisco Silva-Agüero, Lisa M Ellerby.

The intestinal epithelium serves as an essential interface between the host and microbiota, regulating innate and adaptive immunity, absorption of nutrients and systemic metabolism, and mediating bidirectional communication with the nervous system. The intestinal epithelium suffers constant challenges to the proteostasis machinery due to its exposure to the dynamically changing and microbial laden lumenal gut environment and to the high secretory demand placed on multiple epithelial cell types to accommodate gut and systemic physiology-especially goblet, enteroendocrine and Paneth cells. In all cases, intestinal cells require an active unfolded protein response (UPR) to sustain their physiological function, the main pathway that monitors and adjusts secretory function changes in the environment. A specialised endoplasmic reticulum (ER) stress sensor uniquely expressed in epithelial cells lining mucosal surfaces, termed inositol-requiring transmembrane kinase/endoribonuclease β, has specific roles in intestinal epithelial homeostasis, regulating mucus production and communication with microbiota. Chronic ER stress or genetic mutations affecting key UPR mediators contribute to the occurrence of inflammatory bowel disease and ulcerative colitis, in addition to colon cancer. Here, we review recent advances linking the UPR and ER stress with gut physiology and intestinal disease. Therapeutic strategies to alleviate ER stress or enforce UPR function to improve intestinal function in ageing and in bowel diseases are also discussed.

Keywords: Crohn's Disease; Digestive System Diseases; Gastrointestinal Diseases; Inflammation; Microbiota

DOI: https://doi.org/10.1136/egastro-2024-100129

Cell Rep. 2025 Feb 12. pii: S2211-1247(25)00068-3. [Epub ahead of print]44(2): 115297

Membrane-tethered SCOTIN condensates elicit an endoplasmic reticulum stress response by sequestering luminal BiP.

Areum Jo, Minkyo Jung, Ji Young Mun, Young Jin Kim, Joo-Yeon Yoo.

The endoplasmic reticulum (ER) stress response controls the balance between cellular survival and death. Here, we implicate SCOTIN, an interferon-inducible ER protein, in activating the ER stress response and modulating cell fate through its proline-rich domain (PRD)-mediated cytosolic condensation. SCOTIN overexpression leads to the formation of condensates enveloping multiple layers of the ER, accompanied by morphological signs of organelle stress. Luminal BiP chaperone proteins are sequestered within these SCOTIN condensates, which elicit ER stress responses. The colocalization of luminal BiP with SCOTIN is strictly contingent upon the PRD-mediated condensation of SCOTIN in the cytosolic compartment, closely associated with the ER membrane. The cysteine-rich domain (CRD) of SCOTIN, along with the condensation-prone PRD domain, is required for ER stress induction. We propose that membrane-associated condensation transduces signals across the ER membrane, leading to the induction of BiP assembly and the ER stress response.

Keywords: CP: Cell biology; ER stress; SCOTIN; SHISA-5; biomolecular condensate; cell death; endoplasmic reticulum; phase separation; signal transmission; unfolded protein response

DOI: https://doi.org/10.1016/j.celrep.2025.115297

Adv Exp Med Biol. 2025 ;1468 401-407

Dysregulation of Retinal and Photoreceptor Structural Integrity Genes in ATF6-/- Retinal Organoids.

Allyssa Bradley, Masako Le, Soyeon Park, Heike Kroeger, R Luke Wiseman, Eun-Jin Lee, Jonathan H Lin.

ATF6 is a key regulator of the unfolded protein response (UPR) pathway that maintains cellular homeostasis during ER stress. In people, loss of ATF6 function causes cone dysfunction, manifesting as achromatopsia (ACHM). Previously, we generated ACHM retinal organoids (ROs) from patient induced pluripotent stem cells (iPSCs) carrying mutant ATF6 variants and gene-edited ATF6-knockout (KO) human embryonic stem cells (hESCs). ACHM and ATF6-KO ROs both showed severe stunting of cone inner and outer segments. RNA-Seq analysis of ACHM 290-day-old ROs showed downregulated cone gene expression and dysregulated mitochondria and ER stress gene expression. Here, we analyzed RNA-Seq analysis of 203-day-old ATF6-KO ROs. In younger ROs, we found dysregulation of genes involved in retinal and photoreceptor structural integrity, including CRB1, EGFLAM, and VTN. In addition, we found dysregulation of ATF6 and UPR-regulated transcriptional signatures. Dysregulation of retinal and photoreceptor structural integrity genes may underlie the observed stunting of cone inner/outer segments in ATF6-achromatopsia patients.

Keywords: ATF6; Achromatopsia; Brush border (inner segment/outer segment); Cones; Outer limiting membrane (external limiting membrane); Photoreceptor structure; Retinal organoid; UPR

DOI: https://doi.org/10.1007/978-3-031-76550-6_66

Glia. 2025 Feb 10.

AA147 Alleviates Symptoms in a Mouse Model of Multiple Sclerosis by Reducing Oligodendrocyte Loss.

Metin Aksu, Kevin Kaschke, Joseph R Podojil, MingYi Chiang, Ian Steckler, Kody Bruce, Andrew C Cogswell, Gwen Schulz, Jeffery W Kelly, R Luke Wiseman, Stephen D Miller, Brian Popko, Yanan Chen.

Inflammation-induced oligodendrocyte death and CNS demyelination are key features of multiple sclerosis (MS). Inflammation-triggered endoplasmic reticulum (ER) stress and oxidative stress promote tissue damage in MS and in its preclinical animal model, experimental autoimmune encephalitis (EAE). Compound AA147 is a potent activator of the ATF6 signaling arm of the unfolded protein response (UPR) that can also induce antioxidant signaling through activation of the NRF2 pathway in neuronal cells. Previous work showed that AA147 protects multiple tissues against ischemia/reperfusion damage through ATF6 and/or NRF2 activation; however, its therapeutic potential in neuroinflammatory disorders remains unexplored. Here, we demonstrate that AA147 ameliorated the clinical symptoms of EAE and reduced ER stress, oligodendrocyte loss, and demyelination. Additionally, AA147 suppressed T cells in the CNS without altering the peripheral immune response. Importantly, AA147 significantly increased the expressions of Grp78, an ATF6 target gene, in oligodendrocytes, while enhancing levels of Grp78 as well as Ho-1, an NRF2 target gene, in microglia. In cultured oligodendrocytes, AA147 promoted nuclear translocation of ATF6, but not NRF2. Intriguingly, AA147 altered the microglia activation profile, possibly by triggering the NRF2 pathway. AA147 was not therapeutically beneficial during the acute EAE stage in mice lacking ATF6 in oligodendrocytes, indicating that protection primarily involves ATF6 activation in these cells. Overall, our results suggest AA147 as a potential therapeutic opportunity for MS by promoting oligodendrocyte survival and regulating microglia status through distinct mechanisms.

Keywords: AA147; ATF6; EAE; UPR; oligodendrocyte

DOI: https://doi.org/10.1002/glia.70001

J Exp Med. 2025 Apr 07. pii: e20230173. [Epub ahead of print]222(4):

Loss of ATG7 in microglia impairs UPR, triggers ferroptosis, and weakens amyloid pathology control.

Zhangying Cai, Shoutang Wang, Siyan Cao, Yun Chen, Silvia Penati, Vincent Peng, Carla M Yuede, Wandy L Beatty, Kent Lin, Yiyang Zhu, Yingyue Zhou, Marco Colonna.

Microglia impact brain development, homeostasis, and pathology. One important microglial function in Alzheimer's disease (AD) is to contain proteotoxic amyloid-β (Aβ) plaques. Recent studies reported the involvement of autophagy-related (ATG) proteins in this process. Here, we found that microglia-specific deletion of Atg7 in an AD mouse model impaired microglia coverage of Aβ plaques, increasing plaque diffusion and neurotoxicity. Single-cell RNA sequencing, biochemical, and immunofluorescence analyses revealed that Atg7 deficiency reduces unfolded protein response (UPR) while increasing oxidative stress. Cellular assays demonstrated that these changes lead to lipoperoxidation and ferroptosis of microglia. In aged mice without Aβ buildup, UPR reduction and increased oxidative damage induced by Atg7 deletion did not impact microglia numbers. We conclude that reduced UPR and increased oxidative stress in Atg7-deficient microglia lead to ferroptosis when exposed to proteotoxic stress from Aβ plaques. However, these microglia can still manage misfolded protein accumulation and oxidative stress as they age.

DOI: https://doi.org/10.1084/jem.20230173