The Stress-Inducible Protein DRR1 Exerts Distinct Effects on Actin Dynamics

Abstract

Cytoskeletal dynamics are pivotal to memory, learning, and stress physiology, and thus psychiatric diseases. Downregulated in renal cell carcinoma 1 (DRR1) protein was characterized as the link between stress, actin dynamics, neuronal function, and cognition. To elucidate the underlying molecular mechanisms, we undertook a domain analysis of DRR1 and probed the effects on actin binding, polymerization, and bundling, as well as on actin-dependent cellular processes. Methods: DRR1 domains were cloned and expressed as recombinant proteins to perform in vitro analysis of actin dynamics (binding, bundling, polymerization, and nucleation). Cellular actin-dependent processes were analyzed in transfected HeLa cells with fluorescence recovery after photobleaching (FRAP) and confocal microscopy. Results: DRR1 features an actin binding site at each terminus, separated by a coiled coil domain. DRR1 enhances actin bundling, the cellular F-actin content, and serum response factor (SRF)-dependent transcription, while it diminishes actin filament elongation, cell spreading, and actin treadmilling. We also provide evidence for a nucleation effect of DRR1. Blocking of pointed end elongation by addition of profilin indicates DRR1 as a novel barbed end capping factor. Conclusions: DRR1 impacts actin dynamics in several ways with implications for cytoskeletal dynamics in stress physiology and pathophysiology.

Rapid acting antidepressant (2R,6R)-hydroxynorketamine (HNK) targets glucocorticoid receptor signaling: a longitudinal cerebrospinal fluid proteome study

“…Several other cytoskeletal proteins like Arpc4, Vim, Tubb5, Klkb1, and Msn were also shown to be induced one week after HNK administration. These findings are in line with recent reports indicating the relevance of cytoskeletal dynamics in translating stressful environmental experiences into persistent changes of molecular and cellular function (38, 39). The fact that we identified a considerable number of cytoskeletal proteins to be specifically regulated by HNK (i.e.…”

5‐HT6R null mutatrion induces synaptic and cognitive defects

“…Fam107a is involved in neurite growth, neurodevelopment, and synaptic plasticity (Wang et al, 2019). The Fam107a gene can alter actin dynamics and cognition (Kretzschmar et al, 2018). Our results suggested that various genes involved in cilia formation, synaptic plasticity, and neuronal excitability were altered in 5‐HT6R −/− mouse tissues.…”

“…We observed an abnormal aggregation of spines, which might lead to increased dendritic width. In RNAseq, the Fam107a gene was found to be downregulated, which can alter actin dynamics and impact cognition (Kretzschmar et al, 2018). This finding is consistent with our results above.…”

Anti-Inflammatory Effects of RTD-1 in a Murine Model of Chronic Pseudomonas aeruginosa Lung Infection: Inhibition of NF-κB, Inflammasome Gene Expression, and Pro-IL-1β Biosynthesis

“…In lung tissue homogenates, RTD-1 increased expression of BC055107 ( FAM107a , DDR1 ) by 2.497-fold. This stress-inducible actin-binding protein facilitates regulation of filamentous actin dynamics [ 32 ]. We also found a 2.562-fold increase in NPR3 .…”