Nudel functions in membrane traffic mainly through association with Lis1 and cytoplasmic dynein

Abstract

Nudel and Lis1 appear to regulate cytoplasmic dynein in neuronal migration and mitosis through direct interactions. However, whether or not they regulate other functions of dynein remains elusive. Herein, overexpression of a Nudel mutant defective in association with either Lis1 or dynein heavy chain is shown to cause dispersions of membranous organelles whose trafficking depends on dynein. In contrast, the wild-type Nudel and the double mutant that binds to neither protein are much less effective. Time-lapse microscopy for lysosomes reveals significant reduction in both frequencies and velocities of their minus end–directed motions in cells expressing the dynein-binding defective mutant, whereas neither the durations of movement nor the plus end–directed motility is considerably altered. Moreover, silencing Nudel expression by RNA interference results in Golgi apparatus fragmentation and cell death. Together, it is concluded that Nudel is critical for dynein motor activity in membrane transport and possibly other cellular activities through interactions with both Lis1 and dynein heavy chain.

A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder

“…23 Nudel contributes to the assembly of neurofilaments 26 and to the regulation of microtubular dynamics, 26 and it binds and regulates LIS1, a gene in which mutations are known to cause a severe failure of neuronal migration, resulting in the clinical entity lissencephaly. 31,32 It is therefore possible that the DISC1 frameshift mutation may alter the interaction between DISC1 and Nudel, potentially disrupting neurodevelopmental processes mediated by Nudel. Elimination of the extreme C-terminal coiled-coil domain could also have a more pleiotropic effect on DISC1-mediated signaling, as this domain may be important for the interaction between DISC1 and other proteins.…”

Powering membrane traffic in endocytosis and recycling

“…A bidirectional function of dynein would offer an explanation for the aforementioned inhibition of bidirectional transport on the downregulation of dynein. However, studies of lysosome trafficking in a dynein-binding-defective mutant of mammalian cells do not support this suggestion; although a significant reduction in minus-end-directed movements was detected, plus-end-directed motility was unaltered 86 .…”

Poliovirus Protein 3A Binds and Deregulates LIS1, Causing Block of Membrane Protein Trafficking and Deregulation of Cell Division

“…Poliovirus protein 3A and LIS1 truncation mutants interfere with the ability of LIS1 to participate in the vesicular traffic from the ER to the Golgi. This observation could reflect known properties of LIS1, such as participation of LIS1 in activated microtubule-motor-cargo complexes, 18 in the engagement of motor-cargo with the microtubules, 24,52 or facilitation of dynein departure from the plus ends of microtubules, 43 as well as point to some other possible places of LIS1 activity. Interaction with 3A, which is an ER membrane-bound protein, can anchor LIS1-containing complexes to the cytoplasmic surface of the ER, presumably interfering with those stages of cellular transport activity which take place in the vicinity of the ER, such as protein sorting and organization at ER exit sites, membrane budding and fission, or active prevention of back-fusion of new vesicles with donor membrane.…”

“…58 Neurons are the most sensitive cells to the loss of LIS1 protein activity and decrease in LIS1 amount. 59 On the other hand, NUDEL, LIS1-interacting regulator of various types of dynein activities, including membranous organelle trafficking, 18,60 is important for assembly and transport of neurofilaments; NUDEL deficiency leading to neurodegeneration. 61 The titration of LIS1 by protein 3A could be one of the possible reasons of poliovirus induced neuronal disorder.…”

“…LIS1, encoded by the gene the mutation in which is associated with the type I lissencephaly, 16,17 has been defined as a major cellular interactor of 3A. LIS1 was previously shown to be involved in the dynein motor complex that determines microtubule-associated movement of organelles and membrane vesicles [18][19][20][21][22][23][24][25][26] and maintenance of the integrity of the Golgi apparatus and juxta-centrosomal distribution of its membranes (reviewed in refs. [27][28][29][30][31][32][33][34][35].…”