Regulation of the CUL3 Ubiquitin Ligase by a Calcium-Dependent Co-adaptor

Colleen A McGourty; David Akopian; Carolyn Walsh; Amita Gorur; Achim Werner; Randy Schekman; Diana Bautista; Michael Rape

doi:10.1016/j.cell.2016.09.026

Regulation of the CUL3 Ubiquitin Ligase by a Calcium-Dependent Co-adaptor

Cell. 2016 Oct 6;167(2):525-538.e14. doi: 10.1016/j.cell.2016.09.026.

Authors

Colleen A McGourty¹, David Akopian², Carolyn Walsh¹, Amita Gorur¹, Achim Werner¹, Randy Schekman², Diana Bautista¹, Michael Rape³

Affiliations

¹ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
² Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
³ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: mrape@berkeley.edu.

PMID: 27716508
DOI: 10.1016/j.cell.2016.09.026

Abstract

The ubiquitin ligase CUL3 is an essential regulator of neural crest specification whose aberrant activation has been linked to autism, schizophrenia, and hypertension. CUL3 exerts its roles by pairing with ∼90 distinct substrate adaptors, yet how the different CUL3-complexes are activated is poorly understood. Here, we show that CUL3 and its adaptor KLHL12 require two calcium-binding proteins, PEF1 and ALG2, for recognition of their substrate SEC31. PEF1 and ALG2 form a target-specific co-adaptor that translates a transient rise in cytosolic calcium levels into more persistent SEC31 ubiquitylation, which in turn triggers formation of large COPII coats and promotes collagen secretion. As calcium also instructs chondrocyte differentiation and collagen synthesis, calcium-dependent control of CUL3^KLHL12 integrates collagen secretion into broader programs of craniofacial bone formation. Our work, therefore, identifies both calcium and CUL3 co-adaptors as important regulators of ubiquitylation events that control human development.

Keywords: CUL3; SEC31; calcium; endoplasmic reticulum; ubiquitin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
COP-Coated Vesicles / metabolism
Calcium / metabolism*
Calcium-Binding Proteins / metabolism*
Cell Cycle Proteins / metabolism*
Collagen / metabolism
Cullin Proteins / metabolism*
Endosomal Sorting Complexes Required for Transport / metabolism*
HEK293 Cells
Humans
Microfilament Proteins / metabolism*
Substrate Specificity
Ubiquitination
Vesicular Transport Proteins / metabolism

Substances

Adaptor Proteins, Signal Transducing
CUL3 protein, human
Calcium-Binding Proteins
Cell Cycle Proteins
Cullin Proteins
Endosomal Sorting Complexes Required for Transport
KLHL12 protein, human
Microfilament Proteins
PDCD6IP protein, human
PEF1 protein, human
SEC31A protein, human
Vesicular Transport Proteins
Collagen
Calcium