Date of Award

Spring 1-1-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Gia Voeltz

Second Advisor

Jingshi Shen

Third Advisor

Amy Palmer

Fourth Advisor

William Old

Fifth Advisor

Greg Odorrizi

Abstract

The endoplasmic reticulum is the cell’s platform for protein and lipid synthesis. Not only does the ER perform these functions, but it also regulates other organelles through membrane contact sites. To better understand the functions of ER membrane contact sites (MCSs), we optimized tools to monitor contact sites and identify new proteins at these MCSs. We recently showed ER MCSs mark positions of the fission of other organelles. To define the role of ER at this unique MCS, we targeted a promiscuous biotin ligase to the endosome budding domains that form from the endosome body and undergo fission from the endosome for cargo recycling. This strategy identified the ER membrane protein TMCC1, a member of a conserved protein family. TMCC1 concentrates at ER-endosome MCSs that are spatially and temporally linked to endosome fission. When TMCC1 is depleted, endosome morphology is normal, buds still form, but ER-associated bud fission and cargo sorting to the Golgi are impaired. We find that the endosome-localized actin regulator Coronin1C is required for ER-associated fission of actin-dependent cargo sorting domains. Coronin1C is recruited to endosome buds independently of TMCC1, while TMCC1/ER recruitment requires Coronin1C. This link between TMCC1 and Coronin1C suggests a regulated timing of TMCC1-dependent ER recruitment.

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