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News and Views
How cells coordinate waste removal through their major proteolytic pathways Sascha Martens & Andreas Bachmair
The eukaryotic cell uses two complex machineries to degrade unwanted proteins. The first is
the ubiquitin–proteasome system and the second is autophagy. A new study contributes to our
understanding of how the two systems interconnect to coordinate protein degradation.
Rubicon swaps autophagy for LAP
Keith B. Boyle & Felix Randow
Phagocytic cells engulf their prey into vesicular structures called phagosomes, of which a
certain proportion becomes demarcated for enhanced maturation by a process called LC3associated phagocytosis (LAP). Light has now been shed on the molecular requirements of LAP,
establishing a central role for the protein Rubicon in the immune response to Aspergillus
fumigatus.
Super-resolution links vinculin localization to function in focal adhesions
Grégory Giannone
Integrin-based focal adhesions integrate biochemical and biomechanical signals from the
extracellular matrix and the actin cytoskeleton. The combination of three-dimensional superresolution imaging and loss- or gain-of-function protein mutants now links the nanoscale
dynamic localization of proteins to their activation and function within focal adhesions.
News and Views
How cells coordinate waste removal through their major proteolytic pathways Sascha Martens & Andreas Bachmair
Article
Amino-terminal arginylation targets endoplasmic reticulum chaperone BiP for autophagy
through p62 binding
Hyunjoo Cha-Molstad,1, n1 Ki Sa Sung,2, 3, n1 Joonsung Hwang,1, n1 Kyoung A. Kim,1, n1 Ji Eun Yu,1, 4,
Young Dong Yoo,2, Jun Min Jang,5, n2 Dong Hoon Han,6, Michael Molstad,2, Jung Gi Kim,1, Yoon
Jee Lee,2, Adriana Zakrzewska,3, Su-Hyeon Kim,1, Sung Tae Kim,2, 3, Sun Yong Kim,7, Hee Gu Lee,8,
Nak Kyun Soung,1, Jong Seog Ahn,9, Aaron Ciechanover,2, 10, Bo Yeon Kim1, & Yong Tae Kwon2, 11,
We show that ATE1-encoded Arg-transfer RNA transferase (R-transferase) of the N-end rule
pathway mediates N-terminal arginylation of multiple endoplasmic reticulum (ER)-residing
chaperones, leading to their cytosolic relocalization and turnover. N-terminal arginylation of BiP
(also known as GRP78), protein disulphide isomerase and calreticulin is co-induced with
autophagy during innate immune responses to cytosolic foreign DNA or proteasomal inhibition,
associated with increased ubiquitylation. Arginylated BiP (R-BiP) is induced by and associated
with cytosolic misfolded proteins destined for p62 (also known as sequestosome 1, SQSTM1)
bodies. R-BiP binds the autophagic adaptor p62 through the interaction of its N-terminal
arginine with the p62 ZZ domain. This allosterically induces self-oligomerization and
aggregation of p62 and increases p62 interaction with LC3, leading to p62 targeting to
autophagosomes and selective lysosomal co-degradation of R-BiP and p62 together with
associated cargoes. In this autophagic mechanism, Nt-arginine functions as a delivery
determinant, a degron and an activating ligand. Bioinformatics analysis predicts that many ER
residents use arginylation to regulate non-ER processes.
Article
A conserved mechanism of TOR-dependent RCK-mediated mRNA degradation
regulates autophagy
Guowu Hu,1, n1 Travis McQuiston,1, n1 Amélie Bernard,2, n1 Yoon-Dong Park,1, Jin Qiu,1, Ali Vural,3,
Nannan Zhang,1, Scott R. Waterman,1, Nathan H. Blewett,4, Timothy G. Myers,5, Richard J. Maraia,4,
John H. Kehrl,3, Gulbu Uzel,1, Daniel J. Klionsky2, & Peter R. Williamson1,
Autophagy is an essential eukaryotic pathway requiring tight regulation to maintain
homeostasis and preclude disease. Using yeast and mammalian cells, we report a conserved
mechanism of autophagy regulation by RNA helicase RCK family members in association with
the decapping enzyme Dcp2. Under nutrient-replete conditions, Dcp2 undergoes TORdependent phosphorylation and associates with RCK members to form a complex with
autophagy-related (ATG) mRNA transcripts, leading to decapping, degradation and autophagy
suppression. Simultaneous with the induction of ATG mRNA synthesis, starvation reverses the
process, facilitating ATG mRNA accumulation and autophagy induction. This conserved posttranscriptional mechanism modulates fungal virulence and the mammalian inflammasome, the
latter providing mechanistic insight into autoimmunity reported in a patient with a
PIK3CD/p110δ gain-of-function mutation. We propose a dynamic model wherein RCK family
members, in conjunction with Dcp2, function in controlling ATG mRNA stability to govern
autophagy, which in turn modulates vital cellular processes affecting inflammation and
microbial pathogenesis.
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