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Three principal ER quality-control mechanisms, namely, the unfolded protein response, ER-associated degradation (ERAD), and ER-phagy are each important for the maintenance of ER homeostasis, yet how they are integrated to regulate ER homeostasis and organellar architecture in vivo is largely unclear. Here we report intricate crosstalk among the 3 pathways, centered around the SEL1L-HRD1 protein complex of ERAD, in the regulation of organellar organization in β cells. SEL1L-HRD1 ERAD deficiency in β cells triggers activation of autophagy, at least in part, via IRE1α (an endogenous ERAD substrate). In the absence of functional SEL1L-HRD1 ERAD, proinsulin is retained in the ER as high molecular weight conformers, which are subsequently cleared via ER-phagy. A combined loss of both SEL1L and autophagy in β cells leads to diabetes in mice shortly after weaning, with premature death by approximately 11 weeks of age, associated with marked ER retention of proinsulin and β cell loss. Using focused ion beam scanning electron microscopy powered by deep-learning automated image segmentation and 3D reconstruction, our data demonstrate a profound organellar restructuring with a massive expansion of ER volume and network in β cells lacking both SEL1L and autophagy. These data reveal at an unprecedented detail the intimate crosstalk among the 3 ER quality-control mechanisms in the dynamic regulation of organellar architecture and β cell function.

The endoplasmic reticulum (ER) engages mitochondria at specialized ER domains known as mitochondria-associated membranes (MAMs). Here, we used three-dimensional high-resolution imaging to investigate the formation of pleomorphic "megamitochondria" with altered MAMs in brown adipocytes lacking the Sel1L-Hrd1 protein complex of ER-associated protein degradation (ERAD). Mice with ERAD deficiency in brown adipocytes were cold sensitive and exhibited mitochondrial dysfunction. ERAD deficiency affected ER-mitochondria contacts and mitochondrial dynamics, at least in part, by regulating the turnover of the MAM protein, sigma receptor 1 (SigmaR1). Thus, our study provides molecular insights into ER-mitochondrial cross-talk and expands our understanding of the physiological importance of Sel1L-Hrd1 ERAD.

The development and deployment of chatbot technology, while spanning decades and employing different techniques, require innovative frameworks to understand and interrogate their functionality and implications. A mere technocentric account of the evolution of chatbot technology does not fully illuminate how conversational systems are embedded in societal dynamics. This study presents a structured examination of chatbots across three societal dimensions, highlighting their roles as objects of scientific research, commercial instruments, and agents of intimate interaction. Through furnishing a dimensional framework for the evolution of conversational systems — from laboratories to marketplaces to private lives— this article contributes to the wider scholarly inquiry of chatbot technology and its impact in lived human experiences and dynamics. [ABSTRACT FROM AUTHOR]

Three principal ER quality-control mechanisms, namely, the unfolded protein response, ER-associated degradation (ERAD), and ER-phagy are each important for the maintenance of ER homeostasis, yet how they are integrated to regulate ER homeostasis and organellar architecture in vivo is largely unclear. Here we report intricate crosstalk among the 3 pathways, centered around the SEL1L-HRD1 protein complex of ERAD, in the regulation of organellar organization in [beta] cells. SEL1L-HRD1 ERAD deficiency in [beta] cells triggers activation of autophagy, at least in part, via IRE1[alpha] (an endogenous ERAD substrate). In the absence of functional SEL1L-HRD1 ERAD, proinsulin is retained in the ER as high molecular weight conformers, which are subsequently cleared via ER-phagy. A combined loss of both SEL1L and autophagy in [beta] cells leads to diabetes in mice shortly after weaning, with premature death by approximately 11 weeks of age, associated with marked ER retention of proinsulin and [beta] cell loss. Using focused ion beam scanning electron microscopy powered by deep-learning automated image segmentation and 3D reconstruction, our data demonstrate a profound organellar restructuring with a massive expansion of ER volume and network in [beta] cells lacking both SEL1L and autophagy. These data reveal at an unprecedented detail the intimate cross-talk among the 3 ER quality-control mechanisms in the dynamic regulation of organellar architecture and [beta] cell function., Introduction Pancreatic [beta] cells are professional secretory cells capable of synthesizing thousands of proinsulin molecules per second in the ER (1). ER architecture and proteostasis are both highly dynamic and [...]

[beta] Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying [beta] cell loss in type 2 diabetes; however, the molecular drivers underlying such events remain largely unclear. Here, we performed a side-by-side comparison of mice carrying [beta] cell-specific deletion of ER-associated degradation (ERAD) and autophagy. We reported that, while autophagy was necessary for [beta] cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex was required for the maintenance of [beta] cell maturation and identity. Using single-cell RNA-Seq, we demonstrated that Sel1L deficiency was not associated with [beta] cell loss, but rather loss of [beta] cell identity. Sel1L-Hrd1 ERAD controlled [beta] cell identity via TGF-[beta] signaling, in part by mediating the degradation of TGF-[beta] receptor 1. Inhibition of TGF-[beta] signaling in Sel1L-deficient [beta] cells augmented the expression of [beta] cell maturation markers and increased the total insulin content. Our data revealed distinct pathogenic effects of 2 major proteolytic pathways in [beta] cells, providing a framework for therapies targeting distinct mechanisms of protein quality control., Introduction Type 2 diabetes (T2D) is a heterogeneous multicomponent disease, in which disease initiation and progression are triggered and propelled by pancreatic [beta] cell dysfunction and death. Recent studies have [...]

Animals living in caves are of broad relevance to evolutionary biologists interested in understanding the mechanisms underpinning convergent evolution. In the Eastern Andes of Colombia, populations from at least two distinct clades of Trichomycterus catfishes (Siluriformes) independently colonized cave environments and converged in phenotype by losing their eyes and pigmentation. We are pursuing several research questions using genomics to understand the evolutionary forces and molecular mechanisms responsible for repeated morphological changes in this system. As a foundation for such studies, here we describe a diploid, chromosome-scale, long-read reference genome for Trichomycterus rosablanca , a blind, depigmented species endemic to the karstic system of the department of Santander. The nuclear genome comprises 1 Gb in 27 chromosomes, with a 40.0× HiFi long-read genome coverage having an N50 scaffold of 40.4 Mb and N50 contig of 13.1 Mb, with 96.9% (Eukaryota) and 95.4% (Actinopterygii) universal single-copy orthologs (BUSCO). This assembly provides the first reference genome for the speciose genus Trichomycterus , serving as a key resource for research on the genomics of phenotypic evolution. [ABSTRACT FROM AUTHOR]