Mea6 controls VLDL transport through the coordinated regulation of COPII assembly

Abstract

Lipid accumulation, which may be caused by the disturbance in very low density lipoprotein (VLDL) secretion in the liver, can lead to fatty liver disease. VLDL is synthesized in endoplasmic reticulum (ER) and transported to Golgi apparatus for secretion into plasma. However, the underlying molecular mechanism for VLDL transport is still poorly understood. Here we show that hepatocyte-specific deletion of meningioma-expressed antigen 6 (Mea6)/cutaneous T cell lymphoma-associated antigen 5C (cTAGE5C) leads to severe fatty liver and hypolipemia in mice. Quantitative lipidomic and proteomic analyses indicate that Mea6/cTAGE5 deletion impairs the secretion of different types of lipids and proteins, including VLDL, from the liver. Moreover, we demonstrate that Mea6/cTAGE5 interacts with components of the ER coat protein complex II (COPII) which, when depleted, also cause lipid accumulation in hepatocytes. Our findings not only reveal several novel factors that regulate lipid transport, but also provide evidence that Mea6 plays a critical role in lipid transportation through the coordinated regulation of the COPII machinery.

COPII gets in shape: Lessons derived from morphological aspects of early secretion

“…TANGO1 and cTage5 have some overlap in their activities, yet knockout mice of TANGO1 die postpartum, presenting global defects in collagen secretion. In contrast, the deletion of cTage5 is embryonically lethal . Conditional deletion of cTage5 in insulin producing pancreatic beta cells leads to inhibition of proinsulin secretion, suggesting a role of cTage5 in adaptation to high volume secretion .…”

“…Conditional deletion of cTage5 in insulin producing pancreatic beta cells leads to inhibition of proinsulin secretion, suggesting a role of cTage5 in adaptation to high volume secretion . The conditional deletion of cTage5 in the liver, leads to the development of fatty liver and hypolipemia, derived from inhibited secretion of VLDL and attenuated exit of apolipoprotein B100 from the ER . An apoliprotein B receptor was identified as TALI, a fusion between MIA2, which makes up the ER lumenal cargo binding domain and the cytosolic domain of cTage5 (Figure A).…”

“…First, primer proteins potentiate and stabilize the recruitment of the COPII inner layer to facilitate sorting and cargo selection (Figure A,B). Second, primer proteins regulate the recruitment of the coat outer layer onto the inner layer to direct the release of carriers with variable sizes (Figure C) . They do so by controlling the basic assembly reaction of COPII, which is summarized below.…”

“…In the liver, the role of regulated COPII assembly extends beyond the control of VLDL secretion and further exerts selective regulation of lipid synthesis . Here, the linkage between the two COPII layers is regulated by CREB‐regulated transcription coactivator 2 (CRTC2), a transcription coactivator, that binds Sec31A.…”

“…The assembly of cargo‐loaded p24 complexes within a defined lipid environment may also regulate the composition and activity of the recruited coat. Enhancement of Sar1 activation by the recruitment of Sec12 to ERES. TANGO1‐cTage5‐TALI complexes couple PC and apoliprotein B selection with the recruitment of Sec12, enhancing localized Sar1 activation . Localized activation of Sar1 results in the stabilization of the coat inner layer at ERES and supports Sar1 accumulation and assembly for fission and both activities might be critical for the exit of large size cargoes.…”