Yang et al. demonstrate that the goblet cell-expressed microprotein FXYD3 interacts with SERCA2 to regulate ER calcium homeostasis, promoting mucus granule secretion and sialylation. FXYD3 deficiency impairs mucin sialylation and mucus barrier function, increasing susceptibility to intestinal inflammation.

Background: A large number of microproteins (miPs) encoded by small open reading frames (smORFs) are expressed in endothelial cells, yet their function remains largely unknown. In this study, we characterized a novel 46-amino-acid miP encoded by a smORF within the proline-serine-threonine phosphatase interacting protein 2 (PSTPIP2) transcript that was upregulated under inflammatory conditions and we refer to as miP-PSTPIP2. Methods: Immunoprecipitation coupled with mass spectrometry-based proteomics, immunoblotting, immunofluorescence and proximity ligation assays were used to identify and validate miP-PSTPIP2 interacting proteins in human endothelial cells. The impact of adenovirus-mediated overexpression of miP-PSTPIP2 on endocytosis, cytoskeleton dynamics and abundance of proteins involved in these processes was investigated by confocal microscopy and immunoblotting. Live cell imaging was used to assess endothelial cell migration and vascular permeability. Results: miP-PSTPIP2 physically associated with caveolar proteins, proteins involved in the regulation of cytoskeleton dynamics, intracellular transport, clathrin adaptor activity, as well as nuclear proteins. Human endothelial cells overexpressing miP-PSTPIP2 demonstrated enhanced endocytosis and transcytosis of transferrin as well as low-density lipoprotein. Mechanistically, miP-PSTPIP2 modulated Arp2/3-mediated actin nucleation and branching, which are required for dynamic cytoskeleton rearrangements. Moreover, altered cytoskeleton dynamics in miP-PSTPIP2-expressing endothelial cells resulted in impaired cell migration as well as increased permeability and monocyte trans-endothelial migration. Conclusions: miP-PSTPIP2 is an inflammation-induced endothelial miP that regulates Arp2/3-dependent actin dynamics, thereby enhancing lipid uptake and leukocyte permeability. Its upregulation under inflammatory conditions suggests a contributory role in endothelial dysfunction and vascular inflammation.

The microprotein adipogenin (Adig) is predominantly expressed in adipose tissues. Here, we found that Adig interacts with seipin to form a stable, rigid complex. We present the structure of the seipin...

Loss of function of OsPEL microProteins promotes chloroplast development by relieving their cytoplasmic sequestration of OsGLK1 and OsPSA2, enhancing photo

Some small mRNA isoforms regulate cellular responses to stress. Here, Li et al. identify UFD1s, a stress responsive micro-RNA that encodes a conserved microprotein that regulates ubiquitination of full length UFD1, promotes autophagy and fatty acid oxidation, and acts to alleviate NASH progression in mice.

Mitochondria in the fat tissue of mice unable to produce SLC35A4-MP, causing the mitochondria to be structurally compromised and dysfunctional. Credit: Salk Institute Mitochondria in the fat tissue of mice unable to produce SLC35A4-MP, causing the mitochondria to be structurally compromised and dysfunctional. Credit: Salk Institute Like bees breathing life into gardens, providing pollen and making flowers blossom, little cellular machines called mitochondria breathe life into our bodies, buzzing with energy as they produce the fuel that powers each of our cells. Maintaining mitochondrial metabolism requires input from many molecules and proteins—some of which have yet to be discovered.

Like bees breathing life into gardens, providing pollen and making flowers blossom, little cellular machines called mitochondria breathe life into our bodies, buzzing with energy as they produce the fuel that powers each of our cells.

A uORF-encoded microprotein, SLC35A4-MP, modulates mitochondrial morphology and function in brown adipose tissue.