Malin and laforin are essential components of a protein complex that protects cells from thermal stress

Abstract

The heat-shock response is a conserved cellular process characterized by the induction of a unique group of proteins known as heat-shock proteins. One of the primary triggers for this response, at least in mammals, is heat-shock factor 1 (HSF1) – a transcription factor that activates the transcription of heat-shock genes and confers protection against stress-induced cell death. In the present study, we investigated the role of the phosphatase laforin and the ubiquitin ligase malin in the HSF1-mediated heat-shock response. Laforin and malin are defective in Lafora disease (LD), a neurodegenerative disorder associated with epileptic seizures. Using cellular models, we demonstrate that these two proteins, as a functional complex with the co-chaperone CHIP, translocate to the nucleus upon heat shock and that all the three members of this complex are required for full protection against heat-shock-induced cell death. We show further that laforin and malin interact with HSF1 and contribute to its activation during stress by an unknown mechanism. HSF1 is also required for the heat-induced nuclear translocation of laforin and malin. This study demonstrates that laforin and malin are key regulators of HSF1 and that defects in the HSF1-mediated stress response pathway might underlie some of the pathological symptoms in LD.

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

“…55 Important to protein metabolism in neurodegenerative diseases, the laforin-malin complex can suppress cytotoxicity and accumulation of aggregate-prone proteins by interaction with the chaperone proteins, heat-shock protein 70 and C-terminus of Hsc70-interacting protein, to effectively shuttle target proteins to degradation via the proteasome. [56][57][58] Linking LD to autophagy, a recent study provided evidence for a role of laforin in the regulation of autophagy, potentially through the mTOR pathway. 59 In laforin-deficient fibroblasts obtained from patients and in mouse embryonic fibroblasts and liver tissue derived from laforin knockout mice, the levels of the autophagosome marker LC3-II were significantly reduced, indicating compromised autophagosome formation.…”

CHIP Is an Essential Determinant of Neuronal Mitochondrial Stress Signaling

“…The early redox sensors upregulated by OGD, p66 shc and PINK1, associate with mitochondria in response to stress (3,26). Prior studies have only evaluated CHIP distribution in cytosolic and nuclear fractions, the latter of which likely contained mitochondria as the centrifugation speeds noted in the methods are not sufficient enough to efficiently separate these organelles (1,49). Our immunocytochemical analysis revealed a very different pattern of distribution following OGD where CHIP relocates from cytosolic and perinuclear sites to mitochondria.…”

Emerging Roles of Atypical Dual Specificity Phosphatases in Cancer

“…Laforin additionally has a role in stress induced proteostasis [23][24][25][26]. Knock down of Laforin in human embryonic kidney (HEK293) cells and the neuroblastoma cell line, SH-SY5Y, resulted in increased apoptosis induced by endoplasmic reticulum (ER) stress [24].…”

“…In addition to targeting genes involved in glycogen metabolism, recruitment of Malin further promotes ubiquitination of misfolded and aggregated proteins, thereby facilitating their proteosomal degradation [27]. Laforin also interacts with heat shock factor 1 (HSF1), an essential transcription factor in the heat shock response [26] and is necessary for upregulation of HSF1-dependent gene expression and for protection from thermal stress in COS7 cells [26]. Accordingly, increased Laforin expression may allow cancer cells to survive in conditions where proteostasis has been perturbed.…”