VSTM2L is a novel secreted antagonist of the neuroprotective peptide Humanin

Abstract

Humanin (HN) is a 24-residue peptide displaying a protective activity in vitro against a range of cytotoxic and neurotoxic insults, as well as mediating in vivo amelioration of Alzheimer disease (AD)-related memory impairment in experimental models. Published evidence suggests that the mechanisms through which HN exerts its cyto- and neuroprotective activity may include its secretion and binding to membrane-associated receptors. Here, we describe the identification of a new modulator of HN neuroprotective activity, V-set and transmembrane domain containing 2 like (VSTM2L), previously known as C20orf102. VSTM2L interacts with HN in both yeast and mammalian cells, is secreted in cultured cells, is present in serum, and is selectively expressed in the central nervous system. VSTM2L colocalizes with HN in distinct brain areas as well as in primary cultured neurons, where it plays a role in the modulation of neuronal viability. When tested in HN neuroprotection bioassays, VSTM2L acts as a strong antagonist of HN neuroprotective activity. In summary, VSTM2L is the first example of a secreted antagonist of HN and may play a role in the modulation of HN biological functions.

Analyzing the genes related to Alzheimer’s disease via a network and pathway-based approach

“…By applying cell-based studies and FBXO2 knockout mice, it was found that FBXO2 could regulate amyloid precursor protein-related activities in the brain and might modulate AD pathogenesis, coupling with our result to consolidate its involvement in AD [72]. Although no evidence indicated that VSTM2L , one of the intermediate genes, was directly related to AD, it interacted with ataxin 1 ( ATXN1 ) of Alzgset [73], whose biological function is presently unknown, and also might be a secreted antagonist of Humanin ( HN ) [74] which mediated attenuation of AD-related memory impairment and Aβ-induced AD-like pathological changes [75, 76]. As specified by the results detailed, this protein subnetwork predicting approach could not only engender a significant predicted subnetwork of Alzgset for AD, but could also possess the potentiality to detect promising relevant genes.…”

Analysis of key genes and signaling pathways involved in Helicobacter pylori‐associated gastric cancer based on The Cancer Genome Atlas database and RNA sequencing data

“…These results indicated that HDGFRP2 might have a potential suppressive effect on H. pylori ‐associated gastric cancer and may be positively associated with patient survival. VSTM2L, also known as C20orf102, is a novel secreted antagonist of the neuroprotective peptide Humanin and may play a role in the modulation of Humanin biological functions . Its expression varied in brain, gall bladder, and other tissues (heart and stomach, etc.…”

Humanin: Functional Interfaces with IGF-I

“…BH3 interacting-domain death agonist (Bid) and its truncated form (tBid), as well as the extra long isoform of Bim (BimEL) were identified HN binding partners [26,27]. A V-set and transmembrane domain containing two like (VSTM2L) protein has been shown to co-localize with HN in distinct brain regions and primary neurons, where it acts as an antagonist of HN [28]. Actinin-4 and M-phase phosphoprotein 8 (MPP8) have also been identified as HN interacting proteins, however, the biological consequences of their interactions with HN have not been elucidated [29].…”