Plasma cell maintenance and antibody secretion are under the control of Sec22b-mediated regulation of organelle dynamics

Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood. Here, we identified the SNARE Sec22b as a unique and critical regulator of plasma cell maintenance and function. In absence of Sec22b, plasma cells were barely detectable and serum antibody titres were dramatically reduced. Accordingly, Sec22b deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b is indispensable for efficient antibody secretion but also for plasma cell fitness through the regulation of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil a critical role for Sec22b-mediated regulation of plasma cell biology through the control of organelle dynamics.

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases.

Autophagy Regulation on Cancer Stem Cell Maintenance, Metastasis, and Therapy Resistance

Cancer stem cells (CSCs) are a subset of the tumor population that play critical roles in tumorigenicity, metastasis, and relapse. A key feature of CSCs is their resistance to numerous therapeutic strategies which include chemotherapy, radiation, and immune checkpoint inhibitors. In recent years, there is a growing body of literature that suggests a link between CSC maintenance and autophagy, a mechanism to recycle intracellular components during moments of environmental stress, especially since CSCs thrive in a tumor microenvironment that is plagued with hypoxia, acidosis, and lack of nutrients. Autophagy activation has been shown to aid in the upkeep of a stemness state along with bolstering resistance to cancer treatment. However, recent studies have also suggested that autophagy is a double-edged sword with anti-tumorigenic properties under certain circumstances. This review summarizes and integrates what has been published in the literature in terms of what role autophagy plays in stemness maintenance of CSCs and suggests that there is a more complex interplay between autophagy and apoptosis which involves multiple pathways of regulation. Future cancer therapy strategies are needed to eradicate this resistant subset of the cell population through autophagy regulation.

The RNA binding protein Swm is critical for Drosophila melanogaster intestinal progenitor cell maintenance

The regulation of stem cell survival, self-renewal, and differentiation is critical for the maintenance of tissue homeostasis. Although the involvement of signaling pathways and transcriptional control mechanisms in stem cell regulation have been extensively investigated, the role of post-transcriptional control is still poorly understood. Here we show that the nuclear activity of the RNA-binding protein Second Mitotic Wave Missing (Swm) is critical for Drosophila intestinal stem cells (ISCs) and their daughter cells, enteroblasts (EBs), to maintain their identity and function. Loss of swm in these intestinal progenitor cells leads ISCs and EBs to lose defined cell identities, fail to proliferate, and detach from the basement membrane, resulting in severe progenitor cell loss. swm loss further causes nuclear accumulation of poly(A)+ RNA in progenitor cells. Swm associates with transcripts involved in epithelial cell maintenance and adhesion, and the loss of swm, while not generally affecting the levels of these Swm-bound mRNAs, leads to elevated expression of proteins encoded by some of them, including the fly orthologs of Filamin and Talin. Taken together, this study indicates a role for Swm in adult stem cell maintenance, and raises the possibility that nuclear post-transcriptional gene regulation plays vital roles in controlling adult stem cell maintenance and function.

Unraveling the roles of Mast4 in amelogenesis via regulating DLX3 and stem cell maintenance of mouse incisors

Asymmetric division of stem cells allows for maintenance of the cell population and differentiation for harmonious progress. Developing mouse incisors allows for examin ation of how the stem cell niche employs specific insights into essential phases. Microtubule associated serine/threonine kinase family member 4 (Mast4) knockout (KO) mice showed abnormal incisor development with weak hardness as the apical bud was reduced and preameloblasts were shifted to the apical side, resulting in Amelogenesis Imperfecta. In addition, Mast4) KO incisors showed abnormal enamel maturation, and stem cell maintenance was inhibited as amelogenesis accelerated. Distal-Less Homeobox 3 (DLX3), known to be a critical factor Tricho Dento Osseous (TDO) syndrome, is considered to be responsible for A melogenesis Imperfecta in humans. MAST4 directly binds to DLX3 and induces phosphorylation at three residues within the nuclear localization sites (NLS) that promote the nuclear translocation of DLX3. MAST4-mediated phosphorylation of DLX3 ultimately controls the transcription of DLX3 target genes, which are carbonic anhydrase and ion transporter genes involved in the pH regulation process during ameloblast maturation. Taken together, our data reveal a novel role of MAST4 as a critical regulator of ameloblast maturation, which controls DLX3 transcriptional activity.

Non-canonical function of FIP200 is required for neural stem cell maintenance and differentiation by limiting TBK1 activation and p62 aggregate formation

FIP200 is an essential autophagy gene implicated in the regulation of postnatal neural progenitor/stem cells (NSCs). However, the contribution of FIP200’s canonical-autophagy function and its non-canonical functions to postnatal NSC maintenance remains unclear. Utilizing a recently generated Fip200-4A allele that specifically impairs FIP200’s canonical-autophagy function, we found that non-canonical functions of FIP200 was required for regulation of mouse NSC maintenance and neurogenesis in vivo. Ablating the non-canonical functions of FIP200, but not its autophagy function, increased TBK1 activation and p62 phosphorylation at S403 in NSCs. Phosphorylation of p62 was dependent on TBK1 kinase activity and increased the propensity of p62 aggregate formation specifically in FIP200-null NSCs. Accordingly, inhibition of TBK1 by amlexanox reduced p62 aggregates and restored NSC maintenance and differentiation in Fip200hGFAP cKO mice. These results reveal a mechanism for the non-canonical functions of FIP200 in NSC maintenance and differentiation by limiting TBK1 activation and subsequently, p62 aggregate formation.

Convergent evolution of genome guardian functions in a parasite-specific p53 homolog

P53 is a widely studied tumor suppressor that is found throughout metazoans, including invertebrates that do not develop malignancies. The prevailing theory for why this is the case is that P53 originally evolved to protect the germline of early metazoans from genotoxic stress such as UV radiation. In this study, we examine the function of two P53 homologs in the parasitic flatworm Schistosoma mansoni. The first is orthologous to canonical P53, and regulates stem cell maintenance and differentiation. The second P53 gene is a parasite-specific paralog that is required for the normal response to genotoxic stress. This implies that the ability to respond to genotoxic stress in parasitic flatworms may have arisen from convergent evolution.