Coding variants identified in patients with diabetes alter PICK1 BAR domain function in insulin granule biogenesis.
Coding variants identified in patients with diabetes alter PICK1 BAR domain function in insulin granule biogenesis.
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DOI：
10.1172/jci144904
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发表时间：
2022-03-01
期刊：
影响因子：
--
通讯作者：
Madsen KL
中科院分区：
文献类型：
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作者：
Andersen RC;Schmidt JH;Rombach J;Lycas MD;Christensen NR;Lund VK;Stapleton DS;Pedersen SS;Olsen MA;Stoklund M;Noes-Holt G;Nielsen TT;Keller MP;Jansen AM;Herlo R;Pietropaolo M;Simonsen JB;Kjærulff O;Holst B;Attie AD;Gether U;Madsen KL
Bin/amphiphysin/Rvs (BAR) domains are positively charged crescent-shaped modules that mediate curvature of negatively charged lipid membranes during remodeling processes. The BAR domain proteins PICK1, ICA69, and the arfaptins have recently been demonstrated to coordinate the budding and formation of immature secretory granules (ISGs) at the trans-Golgi network. Here, we identify 4 coding variants in the PICK1 gene from a whole-exome screening of Danish patients with diabetes that each involve a change in positively charged residues in the PICK1 BAR domain. All 4 coding variants failed to rescue insulin content in INS-1E cells upon knock down of endogenous PICK1. Moreover, 2 variants showed dominant-negative properties. In vitro assays addressing BAR domain function suggested that the coding variants compromised BAR domain function but increased the capacity to cause fission of liposomes. Live confocal microscopy and super-resolution microscopy further revealed that PICK1 resides transiently on ISGs before egress via vesicular budding events. Interestingly, this egress of PICK1 was accelerated in the coding variants. We propose that PICK1 assists in or complements the removal of excess membrane and generic membrane trafficking proteins, and possibly also insulin, from ISGs during the maturation process; and that the coding variants may cause premature budding, possibly explaining their dominant-negative function.
DOI：
10.1083/jcb.103.3.839
发表时间：
1986-09
期刊：
The Journal of cell biology
影响因子：
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作者：
Tooze J;Tooze SA
通讯作者：
Tooze SA