News and Views

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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 ubiquitinproteasome 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 LC3-associated 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 super-resolution 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.
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News and Views
How cells coordinate waste removal through their
major proteolytic pathways - Sascha Martens
Andreas Bachmair
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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.
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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 TOR-dependent 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
post-transcriptional mechanism modulates fungal
virulence and the mammalian inflammasome, the
latter providing mechanistic insight into
autoimmunity reported in a patient with a
PIK3CD/p110d 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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