Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=29457782
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Kim GH
; Shi G
; Somlo DR
; Haataja L
; Song S
; Long Q
; Nillni EA
; Low MJ
; Arvan P
; Myers MG Jr
; Qi L
J Clin Invest
2018[Mar]; 128
(3
): 1125-1140
PMID29457782
show ga
Pro-opiomelanocortin (POMC) neurons function as key regulators of metabolism and
physiology by releasing prohormone-derived neuropeptides with distinct biological
activities. However, our understanding of early events in prohormone maturation
in the ER remains incomplete. Highlighting the significance of this gap in
knowledge, a single POMC cysteine-to-phenylalanine mutation at position 28
(POMC-C28F) is defective for ER processing and causes early onset obesity in a
dominant-negative manner in humans through an unclear mechanism. Here, we report
a pathologically important role of Sel1L-Hrd1, the protein complex of
ER-associated degradation (ERAD), within POMC neurons. Mice with POMC
neuron-specific Sel1L deficiency developed age-associated obesity due, at least
in part, to the ER retention of POMC that led to hyperphagia. The Sel1L-Hrd1
complex targets a fraction of nascent POMC molecules for ubiquitination and
proteasomal degradation, preventing accumulation of misfolded and aggregated
POMC, thereby ensuring that another fraction of POMC can undergo normal
posttranslational processing and trafficking for secretion. Moreover, we found
that the disease-associated POMC-C28F mutant evades ERAD and becomes aggregated
due to the presence of a highly reactive unpaired cysteine thiol at position 50.
Thus, this study not only identifies ERAD as an important mechanism regulating
POMC maturation within the ER, but also provides insights into the pathogenesis
of monogenic obesity associated with defective prohormone folding.
free
free
free
