عنوان

The Role of Cep78 and NPHP5 in Centrosome Homeostasis

شماره

TL53763

زبان متن نوشتاري يا گفتاري و مانند آن

انگلیسی

عنوان اصلي

The Role of Cep78 and NPHP5 in Centrosome Homeostasis

نام عام مواد

[Thesis]

نام نخستين پديدآور

Hossain, Mohammad Delowar

نام ساير پديدآوران

Tsang, William

نام ناشر، پخش کننده و غيره

McGill University (Canada)

تاریخ نشرو بخش و غیره

2019

متن يادداشت

204 p.

جزئيات پايان نامه و نوع درجه آن

Ph.D.

کسي که مدرک را اعطا کرده

McGill University (Canada)

امتياز متن

2019

متن يادداشت

The centrosome is a microtubule based structure consisting of two centrioles surrounded by electron dense proteinaceous material called the pericentriolar matrix. The two centrioles in each centrosome are identified as mother and daughter centrioles and can be distinguished by the presence of distal and subdistal appendages at the mother centriole. Distal appendages are involved in the docking of the basal body to the cell membrane prior to ciliogenesis. Subdistal appendages are important for the anchoring and nucleation of microtubules, and have recently been found to play an important role in ciliogenesis. The role of centrosome in cells is to organize microtubules, thereby regulating cell shape, motility, polarity and cell migration, as well as act as a template to form the cilia. Cilia are hair-like protrusions found on the surface of the cell membrane that can help with fluid flow, cell locomotion or participate in cell signalling mechanisms based on the type and nature of the cilia. It is known that several diseases such as cancer, microcephaly and ciliopathies are caused by centrosome and cilia abnormalities. A better understanding of the assembly and function of centrosomes and cilia could shed light on many human diseases caused by mutations in the proteins associated with these organelles. Although more than one thousand centrosomal proteins have been identified, the precise role of most of them has not been fully characterized. Here, I have characterized the functions of two centrosomal proteins: Cep78 and NPHP5. Cep78 was previously identified as a novel centrosomal component with no assigned function. I have shown that Cep78 is localized at the distal end of the centriole, suggesting that it carries an important biological function in this region of the centrosome. In addition, Cep78 interacts with VprBP/DCAF1, which is the substrate recognition subunit of both the RING-type CRL4VprBP ubiquitin E3 ligase and the HECT-type EDD-DYRK2-DDB1VprBP ubiquitin E3 ligase. Furthermore, Cep78 specifically binds with EDD-DYRK2-DDB1VprBP, where EDD-DYRK2-DDB1VprBP ubiquitinates and degrades the newly identified substrate CP110. CP110 is known to cap the distal end of the centriole and to suppress centriole elongation. Cep78 preferentially inhibits the ubiquitination activity of EDD-DYRK2-DDB1VprBP, thereby leading to decreased CP110 ubiquitination. Moreover, expression of EDD-DYRK2-DDB1VprBP or depletion of Cep78 promotes centriole elongation, a phenotype reminiscent of CP110 loss. Thus, we found that Cep78 has a role in centrosome homeostasis by regulating the ubiquitination of an EDD-DYRK2-DDB1VprBP substrate. Previously, it has been shown that HIV-1 accessory protein viral protein R (Vpr) interacts with VprBP. As VprBP acts as a substrate recognition subunit of abovementioned two types of ubiquitin E3 ligases, I would like to know if Vpr specifically interacts with EDD-DYRK2-DDB1VprBP in the centrosome. Following up on this work, I found that Vpr interacts with Cep78 in the centrosome through the EDD-DYRK2-DDB1VprBP ubiquitin E3 ligase. Furthermore, I have demonstrated that Vpr and its partner VprBP enhances the ubiquitination and degradation of previously characterized native substrate CP110 without affecting the non-substrate Cep78. Moreover, Vpr mediated loss of CP110 can be overcome by the expression of Cep78. Infection of T-cells with wild type HIV-1 leads to the degradation of CP110, thereby promoting centriole elongation. It is known that the microtubule facilitates HIV-1 trafficking inside the cell. Therefore, our research suggests that Cep78 might counteract the effects of HIV-1 and could play a role in modulating viral pathogenesis.

اصطلاح موضوعی

Cellular biology

اصطلاح موضوعی

Medicine

اصطلاح موضوعی

Molecular biology

مستند نام اشخاص تاييد نشده

Hossain, Mohammad Delowar

مستند نام اشخاص تاييد نشده

Tsang, William

مستند نام تنالگان تاييد نشده

McGill University (Canada)

نام الکترونيکي

فرمت انتشار

p

نوع ماده

[Thesis]

کد کاربرگه

276903

سطح دسترسي

a

تكميل شده

Y