Interaction of SQSTM1 with the motor protein dynein: SQSTM1 is required for normal dynein function and trafficking

Abstract

BSTRACTThe dynein motor protein complex is required for retrograde transport of vesicular cargo and for transport of aggregated proteins along microtubules for processing and degradation at perinuclear aggresomes. Disruption of this process leads to dysfunctional endosome accumulation and increased protein aggregation in the cell cytoplasm, both pathological features of neurodegenerative diseases. However, the exact mechanism of dynein functionality in these pathways is still being elucidated. Here, we show that the scaffolding protein SQSTM1 directly interacts with dynein through a previously unidentified dynein-binding site. This interaction is independent of HDAC6, a known interacting protein of both SQSTM1 and dynein. However, knockdown of HDAC6 increases the interaction of SQSTM1 with dynein, indicating a possible competitive interaction. Using different dynein cargoes, we show that SQSTM1 is required for proper dynein motility and trafficking along microtubules. Based on our results, we propose a new model of competitive interaction between SQSTM1 and HDAC6 with dynein. In this model, SQSTM1 would not only affect the association of polyubiquitylated protein aggregates and endosomes with dynein, but would also be required for normal dynein function.

Metformin increases degradation of phospholamban via autophagy in cardiomyocytes

“…In parallel, we determined whether metformin treatment might affect PLN stability in CMNCs, measured by 35 S-dependent metabolic labeling. Pulse-chase studies showed that the half-lives of wild-type PLN (τ = 9.5 ± 1.2 h) and R9C (τ = 8.8 ± 0.5 h) were similar in transduced CMNCs (Fig.…”

“…HDAC6 is a cytosolic protein that plays a critical role in autophagosome-lysosome fusion; reduced HDAC6 levels are associated with stagnant autophagy and de novo protein aggregation (36). p62 interaction with HDAC6 and its recruitment to the microtubule organization center via dynein is important for dynein motor protein trafficking of ubiquitinylated proteins, as p62-null mouse embryonic fibroblasts become devoid of ubiquitin aggregates along microtubules (35). Taken together, these results can account for PLN translocation to the lysosomes after autophagosome biosynthesis.…”

“…other organelles, including the lysosomes, in murine myoblasts and myotubes (33). p62 has been shown to physically interact with histone deacetylase-6 (HDAC6) (34) and dynein (35). HDAC6 is a cytosolic protein that plays a critical role in autophagosome-lysosome fusion; reduced HDAC6 levels are associated with stagnant autophagy and de novo protein aggregation (36).…”

Acute exposure to organic and inorganic sources of copper: Differential response in intestinal cell lines

“…Indeed, SQSTM1, LC3‐II, and BAG3 have also been implicated in aggresome formation (Calderilla‐Barbosa et al., 2014) and were increased particularly in Cu OAC suggesting aggresome formation. In HT29, dynein, a retrograde transporter carrying aggregates to an aggresome, was increased on Cu OAC treatment.…”

“…The increase in the autophagy adaptor proteins SQSTM1 and LC3-I/LC3-II did not correlate with a block in autophagy or with increased autophagy as there was no increase in autophagy structures (autolysosomes or early autophagic compartments). Indeed, SQSTM1, LC3-II, and BAG3 have also been implicated in aggresome formation (Calderilla-Barbosa et al, 2014) and were increased particularly in Cu OAC suggesting aggresome formation. In HT29, dynein, a retrograde transporter carrying aggregates to an aggresome, was increased on Cu OAC treatment.…”