Myeloid-derived growth factor is a resident endoplasmic reticulum protein

Abstract

Human myeloid-derived growth factor (MYDGF, also known as C19orf10) is named based on its identification as a secreted monocyte/macrophage-derived mediator of cardiac repair following myocardial infarction in mice. Homologs of MYDGF, however, are present in organisms throughout and outside of the animal kingdom, some of which lack hematopoietic and circulatory systems. Moreover, the UPF0556 protein domain, which defines these homologs, lacks a known structure. As a result, the functions and properties of MYDGF are unclear. Our current work was initiated to test whether MYDGF is present in secretory vesicles of eosinophils, as it was recently reported to be abundant in these cells. However, we could not demonstrate secretion and unexpectedly discovered that MYDGF co-localizes with P4HB in the nuclear envelope, which comprises the bulk of endoplasmic reticulum (ER) in eosinophils, and with P4HB and RCAS1 in Golgi. We noted a ubiquitous C-terminal sequence BXEL (B: basic; X: variable residue; E: Glu; L: Leu) that has the potential to retain human MYDGF and its homologs in the ER. To test the functionality of this sequence, we expressed full-length human MYDGF or MYDGF lacking the C-terminal GluLeu residues in monolayers of human embryonic kidney 293 (HEK293) cells. Full-length MYDGF accumulated in cells whereas truncated MYDGF appeared in the medium. These observations reveal that MYDGF resides in the ER and the Golgi and provide a new framework for investigating and understanding this intriguing protein.

Solution structure of human myeloid-derived growth factor suggests a conserved function in the endoplasmic reticulum

“…Our goal in initiating these studies was to determine the solution structure of hMYDGF as a model for other members of the widespread MYDGF/UPF0556 family of proteins and to provide insights into the functions of MYDGF as a well-conserved resident ER protein 1 and as a paracrine/autocrine survival factor with therapeutic potential after myocardial infarction 7,32 . We found that hMYDGF consists of a β-sandwich occluded at one edge by an α-helical turn and small β-sheet (Fig.…”

“…Human myeloid-derived growth factor (hMYDGF) is a member of the widely distributed MYDGF family of proteins found in organisms as distant as protozoans 1 . In humans, MYDGF is abundant in nearly 200 different tissues, fluids, and cell lines as compiled by Proteomics DB, a repository of quantitative proteomics data 2 .…”

“…KDELRs retain target proteins in the ER by engaging a C-terminal ERS at the slightly acidic pH of the Golgi (6.0–6.7) and dissociating under the more neutral pH conditions of the ER (7.2) after retrograde transport 4–6 . Removal of the C-terminal Glu-Leu residues from hMYDGF exogenously expressed in HEK293 cells demonstrated that absence or presence of an intact ERS determines, in a nearly all-or-none fashion, whether hMYDGF is retained in ER or secreted 1 .…”

Crystal structure and receptor-interacting residues of MYDGF — a protein mediating ischemic tissue repair

“…MYDGF, previously named c19orf10 (chromosome 19 open reading frame 10), is a poorly characterized protein, which was identified as a paracrine-acting protein that is secreted by monocytes and macrophages 4 . MYDGF is evolutionarily highly conserved and resides in the endoplasmic reticulum (ER), in the Golgi and extracellularly 6 . According to its primary amino acid sequence, MYDGF does not belong to any known cytokine or growth factor family.…”

“…According to its primary amino acid sequence, MYDGF does not belong to any known cytokine or growth factor family. Human MYDGF has 142 amino acids and consists of an N-terminal 31-residue-long signal peptide and the MYDGF protein sequence containing a C-terminal KDEL-like ER retention sequence 6 . Even though MYDGF’s effects on cardiac tissue repair have been revealed and downstream signaling pathways have been identified 4 , the MYDGF receptor(s) or binding partners mediating these effects remain unknown.…”