Commentary
Abstract
Studies of amyloid-β (Aβ) in Alzheimer’s disease pathology have revealed the peptide’s complex roles in synaptic function. The study by Siddu et al. in this issue clarifies the contexts in which Aβ peptides may be synaptogenic or synaptotoxic. This commentary integrates the study’s major findings with the salient findings of others that, over recent years, have redefined Aβ from a troublesome waste product into a physiological agent of the innate immune response and a modulator of synaptic homeostasis. Convergent evidence demonstrates how free, nonaggregated Aβ supports synaptic structure and activity, whereas oligomeric assemblies enact an adaptive brake on excitatory drive that can become maladaptive with age and inflammation. This redefined perspective on Aβ function emphasizes an evolutionarily conserved feedback loop linking neuronal activity, amyloid generation, and synaptic tuning that protects energy balance under stress but, when dysregulated, promotes proteostatic failure, persistent neuroinflammation, and network dysfunction characteristic of Alzheimer’s disease.
Authors
Joachim Herz
Abstract
Approximately 80% of Merkel cell carcinoma (MCC) cases are caused by Merkel cell polyomavirus (MCV), driven by its T antigen oncogene. Why MCV drives MCC, a skin cancer that displays the neuroendocrine Merkel cell phenotype, remains unclear. In this issue of the JCI, Miao et al. demonstrated that MCC tumor survival requires neuroendocrine-lineage transcription factors, which are recruited to superenhancers (SEs) with the viral small T antigen oncoprotein to promote the neuroendocrine Merkel cell lineage of the cancer. Surprisingly, SEs mapped near the MCV integration site in MCC, and two SE-associated neuroendocrine transcription factors drove viral T antigen gene expression. MCV oncogene and neuroendocrine transcriptional network interactions rendered this viral tumorigenesis dependent on the Merkel cell lineage. Together with reports from other groups, the findings explain why MCV-associated cancer is specifically linked to the Merkel cell phenotype and identify epigenetic strategies targeting of lineage-dependent oncogene circuitry to treat virus-positive MCC.
Authors
Masahiro Shuda
Abstract
The aryl hydrocarbon receptor (AhR) is increasingly recognized as a physiologic modulator of the immune response, a function that extends beyond its established role as a sensor for environmental xenobiotics. In a recent report published in the JCI, Cros et al. demonstrate that the AhR restrains tonic, microbiota-driven inflammatory cytokine production in monocytes. Through the combined use of murine models, human ex vivo systems, and the analysis of patient-derived data, Cros and coworkers established that the AhR limits stimulator of IFN gene–induced (STING-induced) proinflammatory signals. These findings define cell type–specific physiologic roles for the AhR in the regulation of innate immunity and underscore its potential as a therapeutic target for the treatment of inflammatory and autoimmune diseases.
Authors
Jessica E. Kenison, Francisco J. Quintana
Abstract
Loss of circulating insulin resulting from autoimmune destruction of β cells is the defining characteristic of type 1 diabetes (T1D), but islet dysfunction in T1D affects both β cells and α cells. Advances in multiomic analyses and the systematic collection of diseased human pancreata are enabling new approaches for diabetes research; hypotheses can be generated from observations in the affected human tissue and then tested in human islets, stem cell–derived islets, or humanized mice. The study by dos Santos and colleagues that appears in this issue of the JCI is an excellent example of the advantages and challenges posed by this approach. Through integrated analyses that combined electrophysiological and transcriptomic profiling, the authors provided detailed insights into the mechanisms leading to α cell dysfunction in islets from individuals with T1D.
Authors
Decio L. Eizirik, Priscila L. Zimath
Abstract
Type 2 diabetes mellitus affects over 38 million Americans, with diabetic kidney disease as a major complication partly driven by lipotoxicity. Fatty acid transport protein 2 (FATP2) regulates uptake and activation of long-chain fatty acids, making it a therapeutic target in metabolic disease. In this issue of the JCI, Khan et al. investigated FATP2 in glycemic control. In db/db mice, global FATP2 deletion reduced plasma glucose via sustained insulin secretion, with expression restricted to pancreatic α cells. FATP2-deficient db/db mice also showed suppressed glucagon and reduced alanine-stimulated gluconeogenesis, implicating α cell FATP2 in systemic glucose regulation. The FATP2-specific inhibitor lipofermata enhanced α cell–derived glucagon-like peptide 1 (GLP-1) secretion, expanded GLP-1–positive α cell mass, and promoted paracrine insulin release — effects reversed by GLP-1 receptor antagonism. These findings identify FATP2 as a key regulator linking lipid handling to α cell hormone secretion and glucose control, positioning its inhibition as a potential complement to incretin-based therapies.
Authors
Paul N. Black, Concetta C. DiRusso
Abstract
Estrogen receptor α (ESR1) is a pivotal regulator of endometrial homeostasis and reproductive function, yet the coregulators that fine tune its transcriptional activity remain incompletely defined. In this issue of the JCI, Hewitt et al. identified Zinc finger MIZ-type containing 1 (ZMIZ1) as an ESR1 coregulator that is essential for stromal proliferation, decidualization, and overall endometrial integrity. ZMIZ1 deficiency was associated with endometriosis and endometrial cancer, and conditional ablation of Zmiz1 using the PgrCre mouse led to infertility and accelerated fibrosis due to impaired estrogen responsiveness. These findings position ZMIZ1 as a key modulator of estrogen signaling with translational potential as both a biomarker and a therapeutic target in uterine disorders.
Authors
Md Saidur Rahman, Kyeong A So, Jae-Wook Jeong
Abstract
Invasive fungal infections carry high morbidity and mortality, but there are no fungal vaccines. In this issue of the JCI, Okaa et al. report that endonuclease 2 (Eng2), an antigen shared by the Blastomyces, Histoplasma, and Coccidioides species of fungi, elicits protective immunity in mice against blastomycosis, histoplasmosis, and coccidioidomycosis. These results establish a common antigen that can elicit protection against multiple mycoses, encouraging the development of a pan-fungal vaccine. The road to fungal vaccines is made difficult by the need for effectiveness in immunocompromised individuals, the sporadic nature of fungal disease, and the economics of vaccine development. Despite these hurdles, there is optimism that such vaccines can be developed and perhaps find usefulness as adjuncts to antifungal therapy.
Authors
Arturo Casadevall
Abstract
DNA damage and repair are central to the onset of cancer, aging, and aging-related diseases. Rare genetic defects in the nucleotide excision repair pathway, such as those causing the cancer-prone disorder xeroderma pigmentosum (XP) or the progeroid condition Cockayne syndrome, highlight the dramatic consequences of unrepaired DNA lesions. In this issue of the JCI, two related papers from Ogi and coworkers — Fassihi et al. and Nakazawa et al. — describe a new XP clinical entity, XP-J, linked to a pathogenic variant in the p52 subunit of the transcription-repair complex TFIIH. The studies’ characterization of XP-J and the p52ΔC variant opened unexpected possibilities to ameliorate the molecular defect in another subunit of TFIIH that causes a different, more severe repair syndrome: trichothiodystrophy. This commentary provides a broader historical, medical, and molecular context for the intricate genotype-phenotype relationship between compromised repair and its clinical consequences and discusses next steps for the advances reported.
Authors
Arjan F. Theil, Jan H.J. Hoeijmakers
Abstract
Glycogen synthase kinase-3β (GSK3β) is an established regulator in the DNA double-strand break (DSB) repair pathway. Recent work by Allam et al. revealed a mechanism of DSB repair pathway choice through GSK3β-mediated, site-specific phosphorylation of the tumor suppressor p53 binding protein 1 (53BP1) at threonine 334 (T334). 53BP1 T334 phosphorylation prevented interaction between 53BP1 and its downstream functional partners, PTIP and RIF1, thereby inhibiting 53BP1-directed nonhomologous end joining (NHEJ). Additionally, 53BP1 T334 phosphorylation promoted recruitment of CtIP and RPA32 to DNA damage sites to facilitate homologous recombination (HR). In contrast with loss of 53BP1 function, a 53BP1 T334A phospho-deficient mutant accumulated aberrantly at DSBs, where it impaired end resection and suppressed HR activity. These surprising results suggest that GSK3β may select between NHEJ and HR DNA repair pathways. Additionally, these data support targeting the GSK3β/53BP1 axis to enhance PARP inhibitor efficacy in solid tumors, regardless of BRCA1 status.
Authors
Justin W. Leung, David Gius
Abstract
Pulmonary fibrosis, an unrelenting disease of lung scarring, has been associated with the expansion of a profibrotic fibroblast population and extensive extracellular matrix deposition. In this issue, Molina and colleagues provide foundational mechanistic evidence that fibroblast proliferation itself is a critical driver of fibrosis. Using lineage tracing in preclinical fibrosis models, the authors showed that naive Scube2+ alveolar fibroblasts underwent a profibrotic phenotypic switch prior to proliferating within areas of fibrotic remodeling. Induction of apoptosis via Esco2 deletion or directly preventing proliferation via Ect2 deletion in these fibroblasts attenuated fibrosis. Complementary analyses on explanted human lung tissue confirmed translational relevance, collectively providing compelling evidence for the importance of fibroblast proliferation in fibrotic disease.
Authors
Cody A. Schott, Elizabeth F. Redente
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