scholarly journals HYPK scaffolds the Nedd8 and LC3 proteins to initiate the formation of autophagosome around the poly-neddylated huntingtin exon1 aggregates

2019 ◽  
Author(s):  
Debasish Kumar Ghosh ◽  
Ajit Roy ◽  
Akash Ranjan
Keyword(s):  
Regulatory Proteins ◽  
Scaffolding Protein ◽  
Cell Physiology ◽  
Autophagy Flux ◽  
Interacting Protein ◽  
Cellular Autophagy ◽  
Uba Domain ◽  
Autophagic Degradation ◽  
Huntingtin Interacting Protein ◽  
Conserved Amino Acids

ABSTRACTSelective autophagy of protein aggregates is necessary for maintaining the cellular proteostasis. Several regulatory proteins play critical roles in this process. Here, we report that the huntingtin interacting protein K (HYPK) modulates the autophagic degradation of poly-neddylated huntingtin exon1 aggregates. HYPK functions as a scaffolding protein that binds to the Nedd8 and LC3 proteins. The C-terminal ubiquitin-associated (UBA) domain of HYPK binds to the Nedd8, whereas an N-terminal tyrosine-type (Y-type) LC3 interacting region (LIR) of HYPK binds to the LC3. Several conserved amino acids in the UBA domain of HYPK are necessary to mediate the efficient binding of HYPK to Nedd8. The autophagy inducing properties of HYPK are manifested by the increased lipidation of LC3 protein, increased expression of beclin-1 and ATG-5 proteins, and generation of puncta-like granules of LC3 in the HYPK overexpressing cells. Association of the ‘H-granules’ of HYPK with the poly-neddylated huntingtin exon1 aggregates results in the formation of autophagosome around the huntingtin exon1 aggregates, thereby clearing the aggregates by aggrephagy. Poly-neddylation of huntingtin exon1 is required for its autophagic degradation by HYPK. Thus, overexpression of Nedd8 also increases the basal level of cellular autophagy, other than maintaining the autophagy flux. The poly-neddylation dependent autophagic clearance of huntingtin exon1 by HYPK leads to better cell physiology and survival. Taken together, our study describes a novel mechanism of HYPK mediated autophagy of poly-neddylated huntingtin exon1 aggregates.

scholarly journals The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase

2020 ◽  
Vol 6 (40) ◽  
pp. eabb7854 ◽  
Author(s):  
Riyad N. H. Seervai ◽  
Rahul K. Jangid ◽  
Menuka Karki ◽  
Durga Nand Tripathi ◽  
Sung Yun Jung ◽  
...  
Keyword(s):  
Cell Migration ◽  
Actin Filaments ◽  
Actin Polymerization ◽  
Scaffolding Protein ◽  
Actin Binding ◽  
Set Domain ◽  
Interacting Protein ◽  
Lysine Methyltransferase ◽  
Huntingtin Interacting Protein ◽  
In Cells

The methyltransferase SET domain–containing 2 (SETD2) was originally identified as Huntingtin (HTT) yeast partner B. However, a SETD2 function associated with the HTT scaffolding protein has not been elucidated, and no linkage between HTT and methylation has yet been uncovered. Here, we show that SETD2 is an actin methyltransferase that trimethylates lysine-68 (ActK68me3) in cells via its interaction with HTT and the actin-binding adapter HIP1R. ActK68me3 localizes primarily to the insoluble F-actin cytoskeleton in cells and regulates actin polymerization/depolymerization dynamics. Disruption of the SETD2-HTT-HIP1R axis inhibits actin methylation, causes defects in actin polymerization, and impairs cell migration. Together, these data identify SETD2 as a previously unknown HTT effector regulating methylation and polymerization of actin filaments and provide new avenues for understanding how defects in SETD2 and HTT drive disease via aberrant cytoskeletal methylation.

The Sla2p/HIP1/HIP1R family: similar structure, similar function in endocytosis?

2010 ◽  
Vol 38 (1) ◽  
pp. 187-191 ◽  
Author(s):  
Irit Gottfried ◽  
Marcelo Ehrlich ◽  
Uri Ashery
Keyword(s):  
Interacting Protein ◽  
The Past ◽  
Structure And Dynamics ◽  
Binding Partners ◽  
Conserved Domain ◽  
The Family ◽  
Genetic Techniques ◽  
Close Relatives ◽  
Biochemical Imaging ◽  
Huntingtin Interacting Protein

HIP1 (huntingtin interacting protein 1) has two close relatives: HIP1R (HIP1-related) and yeast Sla2p. All three members of the family have a conserved domain structure, suggesting a common function. Over the past decade, a number of studies have characterized these proteins using a combination of biochemical, imaging, structural and genetic techniques. These studies provide valuable information on binding partners, structure and dynamics of HIP1/HIP1R/Sla2p. In general, all suggest a role in CME (clathrin-mediated endocytosis) for the three proteins, though some differences have emerged. In this mini-review we summarize the current views on the roles of these proteins, while emphasizing the unique attributes of each family member.

PTPIP51 crosslinks the NFκB signaling and the MAPK pathway in SKBR3 cells and provides a bypass mechanism for NFκB inhibition

2019 ◽  
Author(s):  
Eric Dietel ◽  
Alexander Brobeil ◽  
Claudia Tag ◽  
Stefan Gattenloehner ◽  
Monika Wimmer
Keyword(s):  
Breast Cancer ◽  
Cell Viability ◽  
Mapk Pathway ◽  
Tyrosine Phosphatase ◽  
Large Body ◽  
Therapy Resistance ◽  
Mapk Signaling ◽  
Scaffolding Protein ◽  
Hacat Cells ◽  
Interacting Protein

Abstract Background Previous studies of our group revealed an association of the scaffolding protein Protein Tyrosine Phosphatase Interacting Protein 51 (PTPIP51) with the NFκB signaling on the RelA and IκB level. The NFκB signaling plays a pivotal role in many different tumor entities. Especially HER2 amplified breast cancer cells frequently display activation of the NFκB signaling. Here, the NFκB signaling is linked to the initiation, progression, and the metastasis of the breast cancer. Furthermore, a large body of evidence associates the NFκB signaling with the development of therapy resistance. We aimed to clarify the effects of NFκB inhibition on the NFκB- and the MAPK-related interactome of PTPIP51 in HaCat cells and SKBR3 cells and their correlation with cell viability. Results Both NFκB signaling inhibitors, PDTC and IKK-16, reduced the cell viability of SKBR3 cells. IKK-16 selectively reduced the cell viability in SKBR3 cells at 5µM, while the viability of HaCat cells was not affected. PDTC impaired the cell viability of both cell lines and induced a formation of the Raf1/14-3-3/PTPIP51 complex in SKBR3 cells, indicating a shift of PTPIP51 into MAPK signaling. The MAPK-related interactome of PTPIP51 remained unaffected by IKK-16. Conclusion (1)The effectiveness and selectivity of NFκB inhibition in malignant and non-malignant signaling systems depends on the level of the targeted signaling molecule. (2) PTPIP51 might serve as the mediator between the NFκB signaling and the MAPK pathway in SKBR3 cells upon NFκB inhibition.

Huntingtin interacting protein HYPK is intrinsically unstructured

2007 ◽  
Vol 71 (4) ◽  
pp. 1686-1698 ◽  
Author(s):  
Swasti Raychaudhuri ◽  
Pritha Majumder ◽  
Somosree Sarkar ◽  
Kalyan Giri ◽  
Debashis Mukhopadhyay ◽  
...  
Keyword(s):  
Interacting Protein ◽  
Huntingtin Interacting Protein

Identification of the Full-Length Huntingtin- Interacting Protein p231HBP/HYPB as a DNA-Binding Factor

2001 ◽  
Vol 18 (1) ◽  
pp. 68-79 ◽  
Author(s):  
Susanne Rega ◽  
Thorsten Stiewe ◽  
Dae-In Chang ◽  
Barbara Pollmeier ◽  
Helmut Esche ◽  
...  
Keyword(s):  
Dna Binding ◽  
Full Length ◽  
Interacting Protein ◽  
Binding Factor ◽  
Huntingtin Interacting Protein

scholarly journals Huntingtin Interacting Protein 1 Induces Apoptosis via a Novel Caspase-dependent Death Effector Domain

2000 ◽  
Vol 275 (52) ◽  
pp. 41299-41308 ◽  
Author(s):  
Abigail S. Hackam ◽  
Ayman S. Yassa ◽  
Roshni Singaraja ◽  
Martina Metzler ◽  
Claire-Anne Gutekunst ◽  
...  
Keyword(s):  
Interacting Protein ◽  
Effector Domain ◽  
Death Effector Domain ◽  
Huntingtin Interacting Protein 1 ◽  
Death Effector ◽  
Huntingtin Interacting Protein

scholarly journals Huntingtin-interacting protein 14, a palmitoyl transferase required for exocytosis and targeting of CSP to synaptic vesicles

2007 ◽  
Vol 179 (7) ◽  
pp. 1481-1496 ◽  
Author(s):  
Tomoko Ohyama ◽  
Patrik Verstreken ◽  
Cindy V. Ly ◽  
Tanja Rosenmund ◽  
Akhila Rajan ◽  
...  
Keyword(s):  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Protein Localization ◽  
Low Frequency ◽  
Chimeric Protein ◽  
Interacting Protein ◽  
Low Frequency Stimulation ◽  
Frequency Stimulation ◽  
And Function ◽  
Huntingtin Interacting Protein

Posttranslational modification through palmitoylation regulates protein localization and function. In this study, we identify a role for the Drosophila melanogaster palmitoyl transferase Huntingtin-interacting protein 14 (HIP14) in neurotransmitter release. hip14 mutants show exocytic defects at low frequency stimulation and a nearly complete loss of synaptic transmission at higher temperature. Interestingly, two exocytic components known to be palmitoylated, cysteine string protein (CSP) and SNAP25, are severely mislocalized at hip14 mutant synapses. Complementary DNA rescue and localization experiments indicate that HIP14 is required solely in the nervous system and is essential for presynaptic function. Biochemical studies indicate that HIP14 palmitoylates CSP and that CSP is not palmitoylated in hip14 mutants. Furthermore, the hip14 exocytic defects can be suppressed by targeting CSP to synaptic vesicles using a chimeric protein approach. Our data indicate that HIP14 controls neurotransmitter release by regulating the trafficking of CSP to synapses.

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