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Lysosomal enzymes are synthesized in the endoplasmic reticulum (ER) and transferred to the Golgi complex by interaction with the Batten disease protein CLN8 (ceroid lipofuscinosis, neuronal, 8). Here we investigated the relationship of this pathway with CLN6, an ER-associated protein of unknown function that is defective in a different Batten disease subtype. Experiments focused on protein interaction and trafficking identified CLN6 as an obligate component of a CLN6-CLN8 complex (herein referred to as EGRESS: ER-to-Golgi relaying of enzymes of the lysosomal system), which recruits lysosomal enzymes at the ER to promote their Golgi transfer. Mutagenesis experiments showed that the second luminal loop of CLN6 is required for the interaction of CLN6 with the enzymes but dispensable for interaction with CLN8. In vitro and in vivo studies showed that CLN6 deficiency results in inefficient ER export of lysosomal enzymes and diminished levels of the enzymes at the lysosome. Mice lacking both CLN6 and CLN8 did not display aggravated pathology compared with the single deficiencies, indicating that the EGRESS complex works as a functional unit. These results identify CLN6 and the EGRESS complex as key players in lysosome biogenesis and shed light on the molecular etiology of Batten disease caused by defects in CLN6.

This study aimed to determine how the muscle mass of the lower leg affects the preservation of the lower extremities in patients with diabetic foot ulcer. This study analyzed patients with diabetic foot ulcer between January 2014 and June 2018 with a follow-up of at least 2 years. Of these 181 patients whose ulcer is located distal to the metatarsophalangeal joint, which was categorized as grade ≤2 by the Wagner classification were classified into 4 grades: grade 0 (treated without amputation), grade 1 (amputation distal to the metatarsophalangeal joint), grade 2 (Ray, transmetatarsal, Lisfranc, and Chopart amputation), and grade 3 (Syme, below-knee, and above-knee amputation) according to the final amputation degree. The muscles of the lower leg were classified into 4 compartments: anterior, lateral, deep posterior, and superficial posterior. The cross-sectional area and attenuation to estimate the muscle volume and density were measured at the axial image of computed tomography (CT) angiography. No significant differences were observed in the sex ratio and mean age among the grades (P =.966 and.962). The cross-sectional area of the anterior, lateral, and posterior compartments demonstrated no significant differences, but that of the superficial posterior compartment exhibited significant differences among the grades (P <.001). Moreover, the attenuation of the anterior, lateral, and deep posterior compartments showed no significant differences, but that of the posterior compartment showed significant differences among the grades (P =.003). The muscle mass of the superficial posterior compartment of the lower leg could be a good indicator of the preservation of the lower extremity in patients with diabetic foot ulcer. Therefore, a strengthening exercise for the triceps surae and plantaris muscles in the early stage could help preserve as much of the lower extremities as possible. [ABSTRACT FROM AUTHOR]

MYC (also known as c-MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its protumorigenic functions have been attributed to its ability to regulate gene expression programs (1-3). Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts (4-7). While such increases in RNA and protein production may endow cancer cells with pro-tumour hallmarks, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly (8). Here we discover that the spliceosome is a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (such as SF3B1 and U2AF1) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor messenger RNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacological inhibition of the spliceosome in vivo impairs survival, tumorigenicity and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers., To discover genes and cellular processes required to tolerate oncogenic MYC expression, we previously performed a genome-wide MYC-synthetic lethal screen in human mammary epithelial cells (HMECs) engineered with an inducible [...]