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Plasma membrane localization of MLC1 regulates cellular morphology and motility.

Mol Brain. 2019 Dec 30;12(1):116
Junmo Hwang 1 , Hung M Vu 2 , Min-Sik Kim 2 , Hyun-Ho Lim 3
Junmo Hwang 1 , Hung M Vu 2 , Min-Sik Kim 2 , Hyun-Ho Lim 3

[No authors listed]

Author information
  • 1 Molecular Physiology and Biophysics Laboratory, Neurovascular Unit Research Group, Korea Brain Research Institute (KBRI), 41062, Daegu, Republic of Korea.
  • 2 Department of New Biology, Daegu Gyeongbuk Institute of Science & Technology (DGIST), 42988, Daegu, Republic of Korea.
  • 3 Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST), 42988, Daegu, Republic of Korea. hhlim@kbri.re.kr.

摘要


BACKGROUND:Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare form of infantile-onset leukodystrophy. The disorder is caused primarily by mutations of MLC1 that leads to a series of phenotypic outcomes including vacuolation of myelin and astrocytes, subcortical cysts, brain edema, and macrocephaly. Recent studies have indicated that functional interactions among MLC1, GlialCAM, and ClC-2 channels play key roles in the regulation of neuronal, glial and vascular homeostasis. However, the physiological role of MLC1 in cellular homeostatic communication remains poorly understood. In the present study, we investigated the cellular function of MLC1 and its effects on cell-cell interactions. METHODS:MLC1-dependent cellular morphology and motility were analyzed by using confocal and live cell imaging technique. Biochemical approaches such as immunoblotting, co-immunoprecipitation, and surface biotinylation were conducted to support data. RESULTS:We found that the altered MLC1 expression and localization led to a great alteration in cellular morphology and motility through actin remodeling. MLC1 overexpression induced filopodia formation and suppressed motility. And, MLC1 proteins expressed in patient-derived MLC1 mutants resulted in trapping in the ER although no changes in morphology or motility were observed. Interestingly knockdown of Mlc1 induced Arp3-Cortactin interaction, lamellipodia formation, and increased the membrane ruffling of the astrocytes. These data indicate that subcellular localization of expressed MLC1 at the plasma membrane is critical for changes in actin dynamics through complex. Thus, our results suggest that misallocation of pathogenic mutant MLC1 may disturbs the stable cell-cell communication and the homeostatic regulation of astrocytes in patients with MLC.

KEYWORDS: Actin remodeling, Cell motility, Filopodia, Lamellipodia, Leukodystrophy, MLC1