Early Bioinformatic Implication of Triacidic Amino Acid Motifs in Autophagy-Dependent Unconventional Secretion of Mammalian Proteins

Abstract

Several proteins are secreted outside the cell, and in many cases, they may be identified by a characteristic signal peptide. However, more and more studies point to the evidence for an “unconventional” secretion, where proteins without a hitherto unknown signal are secreted, possibly in conditions of starvation. In this work, we analyse a set of 202 RNA binding mammalian proteins, whose unconventional secretion has recently been established. Analysis of these proteins secreted by LC3 mediation, the largest unconventionally secreted dataset to our knowledge, identifies the role of KKX motif as well as triacidic amino acid motif in unconventional secretion, the latter being an extension of the recent implicated diacidic amino acid motif. Further data analysis evolves a hypothesis on the sequence or structural proximity of the triacidic or KKX motifs to the LC3 interacting region, and a phosphorylatable amino acid such as serine as a statistically significant feature among these unconventionally secreted proteins. This hypothesis, although needs to be validated in experiments that challenge the specific details of each of these aspects, appears to be one of the early steps in defining what may be a plausible signal for unconventional protein secretion.

Leaderless secretory proteins of the neurodegenerative diseases via TNTs: a structure-function perspective

“…Incidentally, several parallel reports suggest the secretion of many RNA-binding proteins (~204) that are microtubule-associated protein light chain 3 (LC3)-mediated, and are termed as LC3-Dependent EV Loading and Secretion (LDELS; Leidal et al, 2020 ; Leidal and Debnath, 2020 ). In a recent extended study of these data sets, Biswal et al (2022) observed that of the 204 proteins, 202 of them were found to be leaderless and it has been suggested that the triacidic motif (EEE/DDD/DEE) is found to occur in a statistically significant proportion. The plausible role of phosphorylatable amino acid and the proximity of LC3-interacting region (LIR) in autophagy-dependent unconventional protein secretion has been reported.…”