Loss of malin, but not laforin, results in compromised autophagic flux and proteasomal dysfunction in cells exposed to heat shock

Abstract

Heat stress to a cell leads to the activation of heat shock response, which is required for the management of misfolded and unfolded proteins. Macroautophagy and proteasome-mediated degradation are the two cellular processes that degrade polyubiquitinated, misfolded proteins. Contrasting pieces of evidence exist on the effect of heat stress on the activation of the above-mentioned degradative pathways. Laforin phosphatase and malin E3 ubiquitin ligase, the two proteins defective in Lafora neurodegenerative disorder, are involved in cellular stress response pathways and are required for the activation of heat shock transcription factorthe heat shock factor 1 (HSF1) -and, consequently, for cellular protection under heat shock. While the role of laforin and malin in the proteolytic pathways is well established, their role in cellular recovery from heat shock was not explored. To address this, we investigated autophagic flux, proteasomal activity, and the level of polyubiquitinated proteins in Neuro2a cells partially silenced for laforin or malin protein and exposed to heat shock. We found that heat shock was able to induce autophagic flux, proteasomal activity and reduce the polyubiquitinated proteins load in the laforin-silenced cells but not in the malin-deficient cells. Loss of malin leads to reduced proteasomal activity in the heat-shocked cells. Taken together, our results suggest a distinct mode of action for laforin and malin in the heat shock-induced proteolytic processes.

Degradation of altered mitochondria by autophagy is impaired in Lafora disease

“…A similar defect in autophagy was later described in malin‐deficient mice ( Epm2b −/−) and in other laforin and malin knockout mice . However, it has been postulated that the impairment in autophagy in LD could be secondary to the accumulation of glycogen , and more recently other groups have even questioned the existence of a general autophagic defect in LD . Here, we found that although an increase in the autophagic response took place, as expected , after treating the cells with CCCP, FCCP or oligomycin plus antimycin A, as well as under starvation conditions (growth in KH medium), the LC3‐II levels were always clearly lower in the fibroblasts from LD patients.…”

USP14 Positively Modulates Head and Neck Squamous Carcinoma Tumorigenesis and Potentiates Heat Shock Pathway through HSF1 Stabilization

“…In this research, we studied the impact of USP14 on the apoptosis of HNSCC, and we researched downstream of the USP14-HSF1 pathway. It has been suggested that HSF1 plays an important role in the death of tumor, and it has been reported that HSF1 can regulate the characteristic change of metabolic flux of glycolysis of cancer cells in vivo [52], so the inhibition of HSF1 activity leads slower proliferation and death of tumor cells. Interestingly, the activation of HSF1 has been associated with the upregulation of several antiapoptotic proteins, including Bcl-xL, MCL-1, and Bcl-2, and the survival rate, so the enhanced expression of these antiapoptotic proteins is shown to be mediated by the HSF 1 molecular chaperone HSP protein and BAG3 [53,54].…”