The Uncharacterized Protein Family 0016 (UPF0016) gathers poorly studied membrane proteins well conserved through evolution that possess one or two copies of the consensus motif Glu-x-Gly-Asp-(Arg/Lys)-(Ser/Thr). Members are found in many eukaryotes, bacteria and archaea. The interest for this protein family arose in 2012 when its human member TMEM165 was linked to the occurrence of Congenital Disorders of Glycosylation (CDGs) when harbouring specific mutations. Study of the UPF0016 family is undergone through the characterization of the bacterium Vibrio cholerae (MneA), cyanobacterium Synechocystis (SynPAM71), yeast Saccharomyces cerevisiae (Gdt1p), plant Arabidopsis thaliana (PAM71 and CMT1), and human (TMEM165) members. These proteins have all been identified as transporters of cations, more precisely of Mn²⁺, with an extra reported function in Ca²⁺ and/or H⁺ transport for some of them. Apart from glycosylation in humans, the UPF0016 members are required for lactation in humans, photosynthesis in plants and cyanobacteria, Ca²⁺ signaling in yeast, and Mn²⁺ homeostasis in the five aforementioned species. The requirement of the UPF0016 members for key physiological processes most likely derives from their transport activity at the Golgi membrane in human and yeast, the chloroplasts membranes in plants, the thylakoid and plasma membranes in cyanobacteria, and the cell membrane in bacteria. In the light of these studies on various UPF0016 members, this family is not considered as uncharacterized anymore and has been renamed the Gdt1 family according to the name of its S. cerevisiae member. This review aims at assembling and confronting the current knowledge in order to identify shared and distinct features in terms of transported molecules, mode of action, structure, etc., as well as to better understand their corresponding physiological roles.

The rapid emergence of antibiotic resistance has caused serious threat to global health. The worldwide search for novel classes of antibiotics to combat multidrug-resistant (MDR) bacteria is barren since about half a century ago. One of the promising strategies to combat the MDR pathogens is the combinational therapy. For instance, trimethoprim and clavulanic acid are routinely used to enhance the efficacies of sulfonamides and β-lactam antibiotics in clinic, respectively. Nevertheless, such adjuvants are specific for certain classes of antibiotics. We hypothesized that the combinational treatments with antibiotic adjuvants targeting the bacterial membrane may potentiate other antibiotics against MDR Gram-negative pathogens. In our recent publication (Song et al., doi: 10.1038/s41564-020-0723-z), we demonstrate a short linear antibacterial peptide SLAP-S25, which potentiates multiple antibiotics with different modes of action against Gram-negative bacteria. The mechanism studies show that SLAP-S25 targets both lipopolysaccharide (LPS) in the outer membrane and phosphatidylglycerol (PG) in the inner membrane of Escherichia coli. The impaired bacterial membrane caused by SLAP-S25 promotes the intracellular accumulation of antibiotics in bacteria. Our results indicate that the bacterial membranes are promising targets for the discovery of new antibiotics or antibiotic adjuvants to combat MDR bacteria associated infections.

Lipid droplets (LDs) are cellular compartments dedicated to the storage of metabolic energy in the form of neutral lipids, commonly known as “fat”. The biogenesis of LDs takes place in the endoplasmic reticulum (ER), but its spatial and temporal organization is poorly understood. How exactly sites of LD formation are selected and the succession of proteins and lipids needed to mediate this process remains to be defined. In our current study we show that the yeast triacylglycerol (TAG)-synthases, Lro1 and Dga1 get recruited to discrete ER subdomains where they initiate TAG synthesis and hence LD formation (Choudhary et al. (2020), J Cell Biol). These ER subdomains are defined by yeast seipin, Fld1, and a regulator of diacylglycerol (DAG) production, Nem1. Both Fld1 and Nem1 are ER proteins which localize at contact sites between the ER and LDs. Interestingly, even in cells lacking LDs, Fld1 and Nem1 show punctate localization at ER subdomains independently of each other, but they are required together to recruit the TAG-synthases and hence create functional sites of LD biogenesis. Fld1/Nem1-containing ER subdomains recruit additional LD biogenesis factors, such as Yft2, Pex30, Pet10 and Erg6, and these membrane domains become enriched in DAG. In conclusion, Fld1 and Nem1 play a crucial role in defining ER subdomains for the recruitment of proteins and lipids needed to initiate LD biogenesis.