Septins: Regulators of Protein Stability

Abstract

Septins are small GTPases that play a role in several important cellular processes. In this review, we focus on the roles of septins in protein stabilization. Septins may regulate protein stability by: (1) interacting with proteins involved in degradation pathways, (2) regulating the interaction between transmembrane proteins and cytoskeletal proteins, (3) affecting the mobility of transmembrane proteins in lipid bilayers, and (4) modulating the interaction of proteins with their adaptor or signaling proteins. In this context, we discuss the role of septins in protecting four different proteins from degradation. First we consider botulinum neurotoxin serotype A (BoNT/A) and the contribution of septins to its extraordinarily long intracellular persistence. Next, we discuss the role of septins in stabilizing the receptor tyrosine kinases EGFR and ErbB2. Finally, we consider the contribution of septins in protecting hypoxia-inducible factor 1α (HIF-1α) from degradation.

The mechanisms of action and use of botulinum neurotoxin type A in aesthetics: Key Clinical Postulates II

“…This localization along the plasma membrane is hypothesized to be a contributing factor to duration of action where it may be less exposed to degradation by proteases leading to greater stability. The specific cause or causes of the stabilization and localization of A1 are not entirely clear, but several hypotheses include reduced susceptibility to the ubiquitination pathway via recruitment of deubiquitinating enzymes, tyrosine phosphorylation, interaction with septins on the cytoskeleton, and, notably, the presence of a dileucine motif near the C terminus which, when mutated, results in significant loss of longevity of action 37‐41 . The BoNT‐A light chain continues to exert its lytic effects upon newly generated SNAP‐25 throughout the LC’s lengthy half‐life of several months, but once it is ultimately degraded inhibition of ACh release resolves very rapidly 33,42,43 …”

“…The specific cause or causes of the stabilization and localization of A1 are not entirely clear, but several hypotheses include reduced susceptibility to the ubiquitination pathway via recruitment of deubiquitinating enzymes, tyrosine phosphorylation, interaction with septins on the cytoskeleton, and, notably, the presence of a dileucine motif near the C terminus which, when mutated, results in significant loss of longevity of action. [37][38][39][40][41] The BoNT-A light chain continues to exert its lytic effects upon newly generated SNAP-25 throughout the LC's lengthy half-life of several months, but once it is ultimately degraded inhibition of ACh release resolves very rapidly. 33,42,43 The binding of BoNT-A to neurons and internalization appears to be irreversible and almost permanent, but the invoked muscle paralysis is only temporary.…”

Mechanisms of Botulinum Toxin Type A Action on Pain

“…It appears that double-leucine motif is the determinant of such BoNT/A localization. The binding of BoNT/A near the synaptic membrane involves interaction with septins, small GTP-ase proteins that polymerize into non-polar filaments to form a part of cytoskeleton [41]. Another possible explanation is that BoNT/A escapes the ubiquitine-proteasome degradation pathway by recruiting specialized enzymes that remove polyubiquitin chains [42].…”

Septins as membrane influencers: direct play or in association with other cytoskeleton partners

“…More broadly, by controlling membrane receptor localization, septins are involved in the regulation of synaptic vesicle trafficking and neurotransmitter release (Ageta-Ishihara et al, 2015;Marttinen et al, 2015). Generally, septins control signaling in diverse cell types by regulating the degradation of PM receptors, such as receptor tyrosine kinases (Vagin and Beenhouwer, 2016).…”