JCB

Autophagy: Zooming in on the source

Cannibalism, although forbidden in most human societies, is part of the everyday life of a cell.  To clear cellular debris and defective organelles or mobilize nutrients in times of deprivation, cells perform a self-eating process called autophagy.  In this process, cellular material is surrounded by an isolation membrane that expands to form an enclosed double-membrane vesicle called the autophagosome.  This structure fuses with lysosomes where the contents are degraded.  The regulation of autophagy in physiological and pathological situations is an area of great interest.  Although many aspects of the membrane biology associated with this process (reviewed in Simonsen and Tooze, (2009)) have been elucidated at a molecular level, the source of the isolation membrane is still a point of contention.   Does it form de novo or is derived from a cellular organelle like the ER?  

Putative autophagic-like vacuoles (asterisks) labeled with a GFP-tagged marker (arrowheads) are observed adjacent to ER membranes (arrows).  Image from Axe et al. (2008).

                                                                                                                                                      Last year, a paper in The JCB from Axe et al. (see also Comment from Simonsen and Stenmark), showed that cup-shaped structures emerging from the ER (termed ‘omegasomes’ due to their shape) act as platforms for the formation of autophagosomes.  Now, a study in Nature Cell Biology (Hayashi-Nishino et al.) adds further support for the ER as the source of this membrane.   In cultured cells, the authors found a close association between the ER and the IM and that this ER-IM shared the same markers as Axe et al’s omegasomes.  They then used electron tomography to zoom in for a 3D view of the ER-IM structure.  This technique showed that a portion of the ER forms a cradle that surrounds the IM and the two structures appear connected.  Elucidating the molecular basis of this interaction will be an important next step.

Hayashi-Nishino et al. (2009) Nat Cell Biol. 11, 1433 - 1437

Simonsen and Tooze (2009) J. Cell Biol. 186(6):773-782

Axe et al. (2009) J. Cell Biol. 182(4):685-701

Simonsen and Stenmark (2008) J. Cell Biol. 182(4):621-622

Kinesin needs a MAP to step in time

The complex choreography of chromosome segregation in anaphase is split into two processes: Anaphase A in which sister chromatids move to opposite spindle poles and Anaphase B in which the spindle elongates.  The latter occurs when overlapping, antiparallel microtubules that constitute the ‘central spindle’ or spindle midzone slide past each other.  The microtubule-associated protein (MAP) PRC1/Ase1 is required for midzone assembly and stability of the anaphase spindle (Khmelinskii et al., 2007; Schuyler et al., 2003).  In work published in The JCB, Scheibel and colleagues (Khmelinskii et al., 2007) showed that in budding yeast Ase1 dephosphorylation by the phosphatase Cdc14 is important for midzone formation and spindle elongation. 

Image from Khmelinskii et al. (2007).  Ase1 (green)
localizes to the spindle midzone in anaphase

                                                                                                                                                                     In the August issue of Developmental Cell, Khmelinskii et al. (2009) present the next step in this story.  They show that Ase1 dephosphorylation promotes its interaction with the kinesin Cin8 thereby recruiting Cin8 to the central spindle where it drives spindle elongation.  This function of Ase1 appears to be conserved in fission yeast as shown by Fu et al. (2009) in the same issue. These studies, together with previous work, show how the timing of Anaphase A and B are coordinated.  In early mitosis, Ase1 is phosphorylated by Cdk1 thereby preventing spindle elongation.  At the metaphase to anaphase transition, separase—which cleaves cohesin to promote sister chromatid separation—activates Cdc14 through the FEAR network.  Cdc14 dephosphorylates Ase1 which moves to the spindle midzone and recruits, in addition to many other proteins, Cin8, which slides antiparallel microtubules apart to promote spindle elongation.   

Khmelinskii et al. (2009) Dev. Cell 17(2):244-56.

Fu et al. (2009) Dev. Cell 17(2):257-67.

Khmelinskii et al. (2007) J. Cell Biol. 177(6):981-93.

Schuyler et al. (2003) J. Cell Biol. 160(4):517-28.