The human signal peptidase complex acts as a quality control enzyme for membrane proteins.

Cells need to detect and degrade faulty membrane proteins to maintain homeostasis. In this study, we identify a previously unknown function of the human signal peptidase complex (SPC)-the enzyme that removes endoplasmic reticulum (ER) signal peptides-as a membrane protein quality control factor. We show that the SPC cleaves membrane proteins that fail to correctly fold or assemble into their native complexes at otherwise hidden cleavage sites, which our study reveals to be abundant in the human membrane proteome. This posttranslocational cleavage synergizes with ER-associated degradation to sustain membrane protein homeostasis and contributes to cellular fitness. Cryptic SPC cleavage sites thus serve as predetermined breaking points that, when exposed, help to target misfolded or surplus proteins for degradation, thereby maintaining a healthy membrane proteome.

Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins.

Mammalian cells can generate amino acids through macropinocytosis and lysosomal breakdown of extracellular proteins, which is exploited by cancer cells to grow in nutrient-poor tumors. Through genetic screens in defined nutrient conditions, we characterized LYSET, a transmembrane protein (TMEM251) selectively required when cells consume extracellular proteins. LYSET was found to associate in the Golgi with GlcNAc-1-phosphotransferase, which targets catabolic enzymes to lysosomes through mannose-6-phosphate modification. Without LYSET, GlcNAc-1-phosphotransferase was unstable because of a hydrophilic transmembrane domain. Consequently, LYSET-deficient cells were depleted of lysosomal enzymes and impaired in turnover of macropinocytic and autophagic cargoes. Thus, LYSET represents a core component of the lysosomal enzyme trafficking pathway, underlies the pathomechanism for hereditary lysosomal storage disorders, and may represent a target to suppress metabolic adaptations in cancer.

Effect of monochloramine treatment on colonization of a hospital water distribution system by Legionella spp.: a 1 year experience study.

Contamination of hot water distribution systems by Legionella represents a great challenge due to difficulties associated with inactivating microorganisms, preserving the water characteristics. The aim of this study was to examine over the course of 1 year in 11 fixed sites, the impact of monochloramine disinfection on Legionella, heterotrophic bacteria (36 °C), Pseudomonas aeruginosa contamination, and chemical parameters of a plumbing system in an Italian hospital. Three days after installation (T0), in the presence of monochloramine concentration between 1.5 and 2 mg/L, 10/11 sites (91%) were contaminated by L. pneumophila serogroups 3 and 10. After these results, the disinfectant dosage was increased to between 6 and 10 mg/L, reducing the level of Legionella by three logarithmic unit by 2 months postinstallation (T2) until 6 months later (T3). One year later (T4), there was a significant reduction (p = 0.0002) at 8/11 (73%) sites. Our data showed also a significant reduction of heterotrophic bacteria (36 °C) in 6/11 (55%) sites at T4 (p = 0.0004), by contrast the contamination of P. aeruginosa found at T0 in two sites persisted up until T4. The results of the present study show that monochloramine is a promising disinfectant that can prevent Legionella contamination of hospital water supplies.